bims-medica 2024-05-26 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–05–26
34 papers selected by
Brett Chrest, East Carolina University

Metabolic Contrasts: Fatty Acid Oxidation and Ketone Bodies in Healthy Brains vs. Glioblastoma Multiforme.
The OGT-c-Myc-PDK2 axis rewires the TCA cycle and promotes colorectal tumor growth.
Mitochondrial bioenergetics as a cell fate rheostat for responsive to Bcl-2 drugs: New cues for cancer chemotherapy.
Identification of Fasnall as a therapeutically effective Complex I inhibitor.
Glucose Regulation of β-Cell KATP Channels: It Is Time for a New Model!
Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium.
Inhibition of lactate dehydrogenase A by diclofenac sodium induces apoptosis in HeLa cells through activation of AMPK.
Take the bull by the horns and tackle the potential downsides of the ketogenic diet.
Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.
The interplay between glucose and ketone bodies in neural stem cell metabolism.
A negative feedback loop underlies the Warburg effect.
AGC1-mediated Metabolic Reprogramming and Autophagy Sustain Survival of Hepatocellular Carcinoma Cells under Glutamine Deprivation.
FLT3-ITD regulation of the endoplasmic reticulum functions in acute myeloid leukemia.
Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC.
Selective eradication of venetoclax-resistant monocytic acute myeloid leukemia with iron oxide nanozymes.
Accounting for NAD Concentrations in Genome-Scale Metabolic Models Captures Important Metabolic Alterations in NAD-Depleted Systems.
Spatial metabolomics using mass-spectrometry imaging to decipher the impact of high red meat diet on the colon metabolome in rat.
Central dogma rates in human mitochondria.
Obesity and overweight are associated with worse survival in early-onset colorectal cancer.
Exploring the Impact of Personalized Nutritional Approaches on Metabolism and Immunity: A Systematic Review of Various Nutrients and Dietary Patterns.
Mass Spectrometric Analysis of Purine Intermediary Metabolism Indicates Cyanide Induces Purine Catabolism in Rabbits.
Direct Infusion Mass Spectrometry to Rapidly Map Metabolic Flux of Substrates Labeled with Stable Isotopes.
Origins of cancer: ain't it just mature cells misbehaving?
Different lactate metabolism subtypes reveal heterogeneity in clinical outcomes and immunotherapy in lung adenocarcinoma patients.
Fluorescence-Guided Spatial Drug Screening in 3D Colorectal Cancer Spheroids.
Excision of the endothelial blood-brain barrier insulin receptor does not alter spatial cognition in mice fed either a chow or high-fat diet.
Physical Activity Decreases Inflammation and Delays Development of Obesity-Associated Pancreatic Ductal Adenocarcinoma.
VDAC1-interacting molecules promote cell death in cancer organoids through mitochondrial-dependent metabolic interference.
Enzymatic depletion of circulating glutamine is immunosuppressive in cancers.
Targeting glutamine metabolism improves sarcoma response to radiation therapy in vivo.
The efficacy of omega-3 fatty acids (O3FAs) as a complementary in colorectal cancer patients: A systematic review and meta-analysis.
Exogenous Ketone Esters as a Potential Therapeutic for Treatment of Sarcopenic Obesity.
Casual associations between blood metabolites and colon cancer.
Metformin as an Enhancer for the Treatment of Chemoresistant CD34+ Acute Myeloid Leukemia Cells.

Int J Mol Sci. 2024 May 17. pii: 5482. [Epub ahead of print]25(10):

Metabolic Contrasts: Fatty Acid Oxidation and Ketone Bodies in Healthy Brains vs. Glioblastoma Multiforme.

Corina Tamas, Flaviu Tamas, Attila Kovecsi, Alina Cehan, Adrian Balasa.

  The metabolism of glucose and lipids plays a crucial role in the normal homeostasis of the body. Although glucose is the main energy substrate, in its absence, lipid metabolism becomes the primary source of energy. The main means of fatty acid oxidation (FAO) takes place in the mitochondrial matrix through β-oxidation. Glioblastoma (GBM) is the most common form of primary malignant brain tumor (45.6%), with an incidence of 3.1 per 100,000. The metabolic changes found in GBM cells and in the surrounding microenvironment are associated with proliferation, migration, and resistance to treatment. Tumor cells show a remodeling of metabolism with the use of glycolysis at the expense of oxidative phosphorylation (OXPHOS), known as the Warburg effect. Specialized fatty acids (FAs) transporters such as FAT, FABP, or FATP from the tumor microenvironment are overexpressed in GBM and contribute to the absorption and storage of an increased amount of lipids that will provide sufficient energy used for tumor growth and invasion. This review provides an overview of the key enzymes, transporters, and main regulatory pathways of FAs and ketone bodies (KBs) in normal versus GBM cells, highlighting the need to develop new therapeutic strategies to improve treatment efficacy in patients with GBM.

Keywords:  carnitine; fatty acids; glioblastoma; ketone bodies; lipid metabolism; β-oxidation

DOI:  https://doi.org/10.3390/ijms25105482
Cell Death Differ. 2024 May 22.

The OGT-c-Myc-PDK2 axis rewires the TCA cycle and promotes colorectal tumor growth.

Huijuan Wang, Jie Sun, Haofan Sun, Yifei Wang, Bingyi Lin, Liming Wu, Weijie Qin, Qiang Zhu, Wen Yi.

Deregulated glucose metabolism termed the "Warburg effect" is a fundamental feature of cancers, including the colorectal cancer. This is typically characterized with an increased rate of glycolysis, and a concomitant reduced rate of the tricarboxylic acid (TCA) cycle metabolism as compared to the normal cells. How the TCA cycle is manipulated in cancer cells remains unknown. Here, we show that O-linked N-acetylglucosamine (O-GlcNAc) regulates the TCA cycle in colorectal cancer cells. Depletion of OGT, the sole transferase of O-GlcNAc, significantly increases the TCA cycle metabolism in colorectal cancer cells. Mechanistically, OGT-catalyzed O-GlcNAc modification of c-Myc at serine 415 (S415) increases c-Myc stability, which transcriptionally upregulates the expression of pyruvate dehydrogenase kinase 2 (PDK2). PDK2 phosphorylates pyruvate dehydrogenase (PDH) to inhibit the activity of mitochondrial pyruvate dehydrogenase complex, which reduces mitochondrial pyruvate metabolism, suppresses reactive oxygen species production, and promotes xenograft tumor growth. Furthermore, c-Myc S415 glycosylation levels positively correlate with PDK2 expression levels in clinical colorectal tumor tissues. This study highlights the OGT-c-Myc-PDK2 axis as a key mechanism linking oncoprotein activation with deregulated glucose metabolism in colorectal cancer.

DOI: https://doi.org/10.1038/s41418-024-01315-4
Cancer Lett. 2024 May 22. pii: S0304-3835(24)00358-6. [Epub ahead of print] 216965

Mitochondrial bioenergetics as a cell fate rheostat for responsive to Bcl-2 drugs: New cues for cancer chemotherapy.

Charlotte Palominos, Sebastián Fuentes-Retamal, Juan Pablo Salazar, Daniela Guzmán-Rivera, Pablo Correa, Mathias Mellado, Ramiro Araya-Maturana, Félix A Urra.

  Pro-survival BCL-2 proteins prevent the initiation of intrinsic apoptosis (mitochondria-dependent pathway) by inhibiting the pro-apoptotic proteins BAX and BAK, while BH3-only proteins promote apoptosis by blocking pro-survival BCL-2 proteins. Disruptions in this delicate balance contribute to cancer cell survival and chemoresistance. Recent advances in cancer therapeutics involve a new generation of drugs known as BH3-mimetics, which are small molecules designed to mimic the action of BH3-only proteins. Promising effects have been observed in patients with hematological and solid tumors undergoing treatment with these agents. However, the rapid emergence of mitochondria-dependent resistance to BH3-mimetics has been reported. This resistance involves increased mitochondrial respiration, altered mitophagy, and mitochondria with higher and tighter cristae. Conversely, mutations in isocitrate dehydrogenase 1 and 2, catalyzing R-2-hydroxyglutarate production, promote sensitivity to Venetoclax. This evidence underscores the urgency for comprehensive studies on bioenergetics-based adaptive responses in both BH3 mimetics-sensitive and -resistant cancer cells. Ongoing clinical trials are evaluating BH3-mimetics in combination with standard chemotherapeutics. In this article, we discuss the role of mitochondrial bioenergetics in response to BH3-mimetics and explore potential therapeutic opportunities through metabolism-targeting strategies.

Keywords:  Mitochondria; Navitoclax; Venetoclax; cancer metabolism; intrinsic apoptosis pathway; mitophagy; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.canlet.2024.216965
bioRxiv. 2024 May 06. pii: 2024.05.03.592013. [Epub ahead of print]

Identification of Fasnall as a therapeutically effective Complex I inhibitor.

Dzmitry Mukha, Jena Dessain, Seamus O'Connor, Katherine Pniewski, Fabrizio Bertolazzi, Jeet Patel, Mary Mullins, Zachary T Schug.

Proliferating cancer cells actively utilize anabolic processes for biomass production, including de novo biosynthesis of amino acids, nucleotides, and fatty acids. The key enzyme of the fatty acid biosynthesis pathway, fatty acid synthase (FASN), is widely recognized as a promising therapeutic target in cancer and other health conditions 1,2 . Here, we establish a metabolic signature of FASN inhibition using a panel of pharmacological inhibitors (GSK2194069, TVB-2640, TVB-3166, C75, cerulenin, and Fasnall). We find that the activity of commonly used FASN inhibitors is inconsistent with the metabolic signature of FASN inhibition (accumulation of malonate, succinate, malonyl coenzyme A, succinyl coenzyme A, and other metabolic perturbations). Moreover, we show that one of these putative FASN inhibitors, Fasnall, is a respiratory Complex I inhibitor that mimics FASN inhibition through NADH accumulation and consequent depletion of the tricarboxylic acid cycle metabolites. We demonstrate that Fasnall impairs tumor growth in several oxidative phosphorylation-dependent cancer models, including combination therapy-resistant melanoma patient-derived xenografts. Fasnall administration does not reproduce neurological side effects in mice reported for other Complex I inhibitors 3,4 . Our results have significant implications for understanding the FASN role in human health and disease and provide evidence of therapeutic potential for Complex I inhibitors with fast systemic clearance. Our findings also highlight the continuing need for validation of small molecule inhibitors to distinguish high-quality chemical probes and to expand the understanding of their application.

DOI: https://doi.org/10.1101/2024.05.03.592013
Diabetes. 2024 Jun 01. 73(6): 856-863

Glucose Regulation of β-Cell KATP Channels: It Is Time for a New Model!

Matthew J Merrins, Richard G Kibbey.

An agreed-upon consensus model of glucose-stimulated insulin secretion from healthy β-cells is essential for understanding diabetes pathophysiology. Since the discovery of the KATP channel in 1984, an oxidative phosphorylation (OxPhos)-driven rise in ATP has been assumed to close KATP channels to initiate insulin secretion. This model lacks any evidence, genetic or otherwise, that mitochondria possess the bioenergetics to raise the ATP/ADP ratio to the triggering threshold, and conflicts with genetic evidence demonstrating that OxPhos is dispensable for insulin secretion. It also conflates the stoichiometric yield of OxPhos with thermodynamics, and overestimates OxPhos by failing to account for established features of β-cell metabolism, such as leak, anaplerosis, cataplerosis, and NADPH production that subtract from the efficiency of mitochondrial ATP production. We have proposed an alternative model, based on the spatial and bioenergetic specializations of β-cell metabolism, in which glycolysis initiates insulin secretion. The evidence for this model includes that 1) glycolysis has high control strength over insulin secretion; 2) glycolysis is active at the correct time to explain KATP channel closure; 3) plasma membrane-associated glycolytic enzymes control KATP channels; 4) pyruvate kinase has favorable bioenergetics, relative to OxPhos, for raising ATP/ADP; and 5) OxPhos stalls before membrane depolarization and increases after. Although several key experiments remain to evaluate this model, the 1984 model is based purely on circumstantial evidence and must be rescued by causal, mechanistic experiments if it is to endure.

DOI: https://doi.org/10.2337/dbi23-0032
Cancer Discov. 2024 May 24.

Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium.

Anagha Inguva Sheth, Mark J Althoff, Hunter Tolison, Krysta Engel, Maria L Amaya, Anna E Krug, Tracy N Young, Mohammad Minhajuddin, Shanshan Pei, Sweta B Patel, Amanda Winters, Regan Miller, Ian T Shelton, Jonathan St-Germain, Tianyi Ling, Courtney L Jones, Brian Raught, Austin E Gillen, Monica Ransom, Sarah Staggs, Clayton A Smith, Daniel A Pollyea, Brett M Stevens, Craig T Jordan.

Acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL-2, creating a therapeutic opportunity to target LSCs using the BCL-2 inhibitor venetoclax. While venetoclax-based regimens have shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug-responsive and non-responsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate a more active metabolic (i.e. OXPHOS) status with relatively high levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter, MCU. We demonstrate that inhibition of calcium uptake reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in LSCs and provide an avenue for clinical management of venetoclax resistance.

DOI: https://doi.org/10.1158/2159-8290.CD-23-1145
FEBS J. 2024 May 20.

Inhibition of lactate dehydrogenase A by diclofenac sodium induces apoptosis in HeLa cells through activation of AMPK.

Avirup Malla, Suvroma Gupta, Runa Sur.

  Cancer cells exhibit a unique metabolic preference for the glycolytic pathway over oxidative phosphorylation for maintaining the tumor microenvironment. Lactate dehydrogenase A (LDHA) is a key enzyme that facilitates glycolysis by converting pyruvate to lactate and has been shown to be upregulated in multiple cancers due to the hypoxic tumor microenvironment. Diclofenac (DCF), a nonsteroidal anti-inflammatory drug, has been shown to exhibit anticancer effects by interfering with the glucose metabolism pathway. However, the specific targets of this drug remain unknown. Using in silico, biochemical, and biophysical studies, we show that DCF binds to LDHA adjacent to the substrate binding site and inhibits its activity in a dose-dependent and allosteric manner in HeLa cells. Thus, DCF inhibits the hypoxic microenvironment and induces apoptosis-mediated cell death. DCF failed to induce cytotoxicity in HeLa cells when LDHA was knocked down, confirming that DCF exerts its antimitotic effects via LDHA inhibition. DCF-induced LDHA inhibition alters pyruvate, lactate, NAD+, and ATP production in cells, and this could be a possible mechanism through which DCF inhibits glucose uptake in cancer cells. DCF-induced ATP deprivation leads to mitochondria-mediated oxidative stress, which results in DNA damage, lipid peroxidation, and apoptosis-mediated cell death. Reduction in intracellular ATP levels additionally activates the sensor kinase, adenosine monophosphate-activated protein kinase (AMPK), which further downregulates phosphorylated ribosomal S6 kinase (p-S6K), leading to apoptosis-mediated cell death. We find that in LDHA knocked down cells, intracellular ATP levels were depleted, resulting in the inhibition of p-S6K, suggesting the involvement of DCF-induced LDHA inhibition in the activation of the AMPK/S6K signaling pathway.

Keywords:  AMPK; ATP; enzyme inhibition; glycolysis; lactate dehydrogenase A

DOI:  https://doi.org/10.1111/febs.17158
Nutrition. 2024 May 02. pii: S0899-9007(24)00130-8. [Epub ahead of print]125 112480

Take the bull by the horns and tackle the potential downsides of the ketogenic diet.

Yiming Meng, Jing Sun, Guirong Zhang.

  The ketogenic diet (KD) is a distinctive dietary regimen known for its low-carbohydrate and high-fat composition. Recently, it has garnered considerable interest from the scientific community and the general population because of its claimed efficacy in facilitating weight reduction, improving the management of glucose levels, and raising overall energy levels. The core principle of the KD is the substantial decrease in carbohydrate consumption, which is subsequently substituted by ingesting nourishing fats. While the KD has promising advantages and is gaining popularity, it must be acknowledged that this dietary method may not be appropriate for all individuals. The dietary regimen may give rise to adverse effects, including constipation, halitosis, and imbalances in electrolyte levels, which may pose a potential risk if not adequately supervised. Hence, thorough and meticulous inquiry is needed to better comprehend the possible hazards and advantages linked to the KD over prolonged durations. By obtaining a more comprehensive perspective, we can enhance our ability to make well-informed judgments and suggestions as to implementation of this specific dietary regimen.

Keywords:  Dexamethasone; Ferroptosis; High-fat; Ketogenic diet; Low-carbohydrate

DOI:  https://doi.org/10.1016/j.nut.2024.112480
Elife. 2024 May 24. pii: RP95652. [Epub ahead of print]13

Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.

Keene L Abbott, Ahmed Ali, Bradley I Reinfeld, Amy Deik, Sonu Subudhi, Madelyn D Landis, Rachel A Hongo, Kirsten L Young, Tenzin Kunchok, Christopher S Nabel, Kayla D Crowder, Johnathan R Kent, Maria Lucia L Madariaga, Rakesh K Jain, Kathryn E Beckermann, Caroline A Lewis, Clary B Clish, Alexander Muir, W Kimryn Rathmell, Jeffrey Rathmell, Matthew G Vander Heiden.

  The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipidomic analyses of tumor interstitial fluid (TIF), adjacent normal kidney interstitial fluid (KIF), and plasma samples collected from patients. TIF nutrient composition closely resembles KIF, suggesting that tissue-specific factors unrelated to the presence of cancer exert a stronger influence on nutrient levels than tumor-driven alterations. Notably, select metabolite changes consistent with known features of RCC metabolism are found in RCC TIF, while glucose levels in TIF are not depleted to levels that are lower than those found in KIF. These findings inform tissue nutrient dynamics in RCC, highlighting a dominant role of non-cancer-driven tissue factors in shaping nutrient availability in these tumors.

Keywords:  cancer; cancer biology; human; metabolism; tumor microenvironment

DOI:  https://doi.org/10.7554/eLife.95652
J Neurosci Res. 2024 May;102(5): e25342

The interplay between glucose and ketone bodies in neural stem cell metabolism.

Joseph W Molloy, Denis Barry.

  Glucose is the primary energy source for neural stem cells (NSCs), supporting their proliferation, differentiation, and quiescence. However, the high demand for glucose during brain development often exceeds its supply, leading to the utilization of alternative energy sources including ketone bodies. Ketone bodies, including β-hydroxybutyrate, are short-chain fatty acids produced through hepatic ketogenesis and play a crucial role in providing energy and the biosynthetic components for NSCs when required. The interplay between glucose and ketone metabolism influences NSC behavior and fate decisions, and disruptions in these metabolic pathways have been linked to neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Additionally, ketone bodies exert neuroprotective effects on NSCs and modulate cellular responses to oxidative stress, energy maintenance, deacetylation, and inflammation. As such, understanding the interdependence of glucose and ketone metabolism in NSCs is crucial to understanding their roles in NSC function and their implications for neurological conditions. This article reviews the mechanisms of glucose and ketone utilization in NSCs, their impact on NSC function, and the therapeutic potential of targeting these metabolic pathways in neurological disorders.

Keywords:  glycolysis; ketone bodies; metabolism; neural stem cell; neurological conditions

DOI:  https://doi.org/10.1002/jnr.25342
NPJ Syst Biol Appl. 2024 May 24. 10(1): 55

A negative feedback loop underlies the Warburg effect.

Alok Jaiswal, Raghvendra Singh.

Aerobic glycolysis, or the Warburg effect, is used by cancer cells for proliferation while producing lactate. Although lactate production has wide implications for cancer progression, it is not known how this effect increases cell proliferation and relates to oxidative phosphorylation. Here, we elucidate that a negative feedback loop (NFL) is responsible for the Warburg effect. Further, we show that aerobic glycolysis works as an amplifier of oxidative phosphorylation. On the other hand, quiescence is an important property of cancer stem cells. Based on the NFL, we show that both aerobic glycolysis and oxidative phosphorylation, playing a synergistic role, are required to achieve cell quiescence. Further, our results suggest that the cells in their hypoxic niche are highly proliferative yet close to attaining quiescence by increasing their NADH/NAD+ ratio through the severity of hypoxia. The findings of this study can help in a better understanding of the link among metabolism, cell cycle, carcinogenesis, and stemness.

DOI: https://doi.org/10.1038/s41540-024-00377-x
Cell Biochem Biophys. 2024 May 24.

AGC1-mediated Metabolic Reprogramming and Autophagy Sustain Survival of Hepatocellular Carcinoma Cells under Glutamine Deprivation.

Yan Liu, Zeyu Miao, Qing Yang.

  The dependence of hepatocellular carcinoma (HCC) cells on glutamine suggests the feasibility of targeting glutamine metabolism for therapy. However, drugs inhibiting glutamine uptake and breakdown have not shown promising outcomes. Therefore, investigating the mechanism of glutamine metabolism reprogramming in HCC cells is crucial. We used bioinformatics approaches to investigate the metabolic flux of glutamine in HCC cells and validated it using qRT-PCR and western blotting. HCC cells were cultured in glutamine-deprived medium, and changes in glutamate and ATP levels were monitored. Western blotting was employed to assess the expression of AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) and autophagy-related proteins. The impact of Solute carrier family 25 member 12 (AGC1) on HCC cell proliferation was studied using CCK-8 and colony formation assays. Furthermore, the effects of AGC1 knockdown via siRNA on metabolic reprogramming and energy supply during glutamine deprivation in HCC were explored. During glutamine deprivation, HCC cells sustain cytosolic asparagine synthesis and ATP production through AGC1. Low ATP levels activate AMPK and inhibit mTOR activation, inducing autophagy to rescue HCC cell survival. Knockdown of AGC1 inhibits mitochondrial aspartate output and continuously activates autophagy, rendering HCC cells more sensitive to glutamine deprivation. AGC1 serves as a critical node in the reprogramming of glutamine metabolism and energy supply in HCC cells. This study provides theoretical support for overcoming resistance to drugs targeting glutamine metabolism.

Keywords:  AGC1; Autophagy; Glutamine deprivation; Hepatocellular carcinoma; Metabolic reprogramming

DOI:  https://doi.org/10.1007/s12013-024-01311-y
Hematol Oncol. 2024 May;42(3): e3281

FLT3-ITD regulation of the endoplasmic reticulum functions in acute myeloid leukemia.

María Turos-Cabal, Ana M Sánchez-Sánchez, Noelia Puente-Moncada, Federico Herrera, Isaac Antolin, Carmen Rodríguez, Vanesa Martín.

  The FLT3-ITD mutation represents the most frequent genetic alteration in newly diagnosed acute myeloid leukemia (AML) patient and is associated with poor prognosis. Mutation result in the retention of a constitutively active form of this receptor in the endoplasmic reticulum (ER) and the subsequent modification of its downstream effectors. Here, we assessed the impact of such retention on ER homeostasis and found that mutant cells present lower levels of ER stress due to the overexpression of ERO1α, one of the main proteins of the protein folding machinery at the ER. Overexpression of ERO1α resulted essential for ITD mutant cells survival and chemoresistance and also played a crucial role in shaping the type of glucose metabolism in AML cells, being the mitochondrial pathway the predominant one in those with a higher ER stress (non-mutated cells) and the glycolytic pathway the predominant one in those with lower ER stress (mutated cells). Our data indicate that FLT3 mutational status dictates the route for glucose metabolism in an ERO1α depending on manner and this provides a survival advantage to tumors carrying these ITD mutations.

Keywords:  ERO1α; FLT3; acute myeloid leukemia; endoplasmic reticulum; glucose metabolism; mitochondria associated membranes

DOI:  https://doi.org/10.1002/hon.3281
Nat Commun. 2024 May 18. 15(1): 4244

Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC.

Nathan P Ward, Sang Jun Yoon, Tyce Flynn, Amanda M Sherwood, Maddison A Olley, Juliana Madej, Gina M DeNicola.

Cysteine metabolism occurs across cellular compartments to support diverse biological functions and prevent the induction of ferroptosis. Though the disruption of cytosolic cysteine metabolism is implicated in this form of cell death, it is unknown whether the substantial cysteine metabolism resident within the mitochondria is similarly pertinent to ferroptosis. Here, we show that despite the rapid depletion of intracellular cysteine upon loss of extracellular cystine, cysteine-dependent synthesis of Fe-S clusters persists in the mitochondria of lung cancer cells. This promotes a retention of respiratory function and a maintenance of the mitochondrial redox state. Under these limiting conditions, we find that glutathione catabolism by CHAC1 supports the mitochondrial cysteine pool to sustain the function of the Fe-S proteins critical to oxidative metabolism. We find that disrupting Fe-S cluster synthesis under cysteine restriction protects against the induction of ferroptosis, suggesting that the preservation of mitochondrial function is antagonistic to survival under starved conditions. Overall, our findings implicate mitochondrial cysteine metabolism in the induction of ferroptosis and reveal a mechanism of mitochondrial resilience in response to nutrient stress.

DOI: https://doi.org/10.1038/s41467-024-48695-2
Biochem Biophys Res Commun. 2024 May 14. pii: S0006-291X(24)00653-3. [Epub ahead of print]719 150117

Selective eradication of venetoclax-resistant monocytic acute myeloid leukemia with iron oxide nanozymes.

Shaoqi Zhang, Shang Lou, Wei Bian, Jun Liu, Rong Wang, Yanan Wang, Yin Zhao, Xiaoqing Zou, Diange Jin, Yue Liang, Jie Sun, Lina Liu.

  The clinical treatment of human acute myeloid leukemia (AML) is rapidly progressing from chemotherapy to targeted therapies led by the BCL-2 inhibitor venetoclax (VEN). Despite its unprecedented success, VEN still encounters clinical resistance. Thus, uncovering the biological vulnerability of VEN-resistant AML disease and identifying effective therapies to treat them are urgently needed. We have previously demonstrated that iron oxide nanozymes (IONE) are capable of overcoming chemoresistance in AML. The current study reports a new activity of IONE in overcoming VEN resistance. Specifically, we revealed an aberrant redox balance with excessive intracellular reactive oxygen species (ROS) in VEN-resistant monocytic AML. Treatment with IONE potently induced ROS-dependent cell death in monocytic AML in both cell lines and primary AML models. In primary AML with developmental heterogeneity containing primitive and monocytic subpopulations, IONE selectively eradicated the VEN-resistant ROS-high monocytic subpopulation, successfully resolving the challenge of developmental heterogeneity faced by VEN. Overall, our study revealed an aberrant redox balance as a therapeutic target for monocytic AML and identified a candidate IONE that could selectively and potently eradicate VEN-resistant monocytic disease.

Keywords:  Acute myeloid leukemia; Iron oxide nanoparticles; ROS; Venetoclax

DOI:  https://doi.org/10.1016/j.bbrc.2024.150117
Biomolecules. 2024 May 20. pii: 602. [Epub ahead of print]14(5):

Accounting for NAD Concentrations in Genome-Scale Metabolic Models Captures Important Metabolic Alterations in NAD-Depleted Systems.

Roland Sauter, Suraj Sharma, Ines Heiland.

  Nicotinamide adenine dinucleotide (NAD) is a ubiquitous molecule found within all cells, acting as a crucial coenzyme in numerous metabolic reactions. It plays a vital role in energy metabolism, cellular signaling, and DNA repair. Notably, NAD levels decline naturally with age, and this decline is associated with the development of various age-related diseases. Despite this established link, current genome-scale metabolic models, which offer powerful tools for understanding cellular metabolism, do not account for the dynamic changes in NAD concentration. This impedes our understanding of a fluctuating NAD level's impact on cellular metabolism and its contribution to age-related pathologies. To bridge this gap in our knowledge, we have devised a novel method that integrates altered NAD concentration into genome-scale models of human metabolism. This approach allows us to accurately reflect the changes in fatty acid metabolism, glycolysis, and oxidative phosphorylation observed experimentally in an engineered human cell line with a compromised level of subcellular NAD.

Keywords:  FBA; NAD; constraint-based model; genome-scale metabolic modeling; proteomics; proteomics integration

DOI:  https://doi.org/10.3390/biom14050602
Talanta. 2024 May 08. pii: S0039-9140(24)00609-X. [Epub ahead of print]276 126230

Spatial metabolomics using mass-spectrometry imaging to decipher the impact of high red meat diet on the colon metabolome in rat.

Justine Ferey, Loïc Mervant, Nathalie Naud, Emilien L Jamin, Fabrice Pierre, Laurent Debrauwer, Françoise Guéraud.

  Colorectal cancer (CRC) is the third most common cancer in the world with a higher prevalence in the developed countries, mainly caused by environmental and lifestyle factors such as diet, particularly red meat consumption. The metabolic impact of high red meat consumption on the epithelial part of the colon was investigated using Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MSI), to specifically analyze the epithelial substructure. Ten colons from rats fed for 100 days high red or white meat diet were subjected to untargeted MSI analyses using two spatial resolutions (100 μm and 10 μm) to evaluate metabolite changes in the epithelial part and to visualize the distribution of metabolites of interest within the epithelium crypts. Our results suggest a specific effect of red meat diet on the colonic epithelium metabolism, as evidenced by an increase of purine catabolism products or depletion in glutathione pool, reinforcing the hypothesis of increased oxidative stress with red meat diet. This study also highlighted cholesterol sulfate as another up-regulated metabolite, interestingly localized at the top of the crypts. Altogether, this study demonstrates the feasibility and the added value of using MSI to decipher the effect of high red meat diet on the colonic epithelium.

Keywords:  Colonic epithelium; Mass spectrometry imaging; Red meat diet; timsTOF

DOI:  https://doi.org/10.1016/j.talanta.2024.126230
Hum Mol Genet. 2024 May 22. 33(R1): R34-R41

Central dogma rates in human mitochondria.

Erik McShane, L Stirling Churchman.

  In human cells, the nuclear and mitochondrial genomes engage in a complex interplay to produce dual-encoded oxidative phosphorylation (OXPHOS) complexes. The coordination of these dynamic gene expression processes is essential for producing matched amounts of OXPHOS protein subunits. This review focuses on our current understanding of the mitochondrial central dogma rates, highlighting the striking differences in gene expression rates between mitochondrial and nuclear genes. We synthesize a coherent model of mitochondrial gene expression kinetics, highlighting the emerging principles and emphasizing where more precise measurements would be beneficial. Such an understanding is pivotal for grasping the unique aspects of mitochondrial function and its role in cellular energetics, and it has profound implications for aging, metabolic disorders, and neurodegenerative diseases.

Keywords:  gene regulation; mitochondrial DNA; mitonuclear balance; oxidative phosphorylation

DOI:  https://doi.org/10.1093/hmg/ddae036
Surgery. 2024 May 20. pii: S0039-6060(24)00202-2. [Epub ahead of print]

Obesity and overweight are associated with worse survival in early-onset colorectal cancer.

Pauline Aeschbacher, Zoe Garoufalia, Justin Dourado, Peter Rogers, Sameh Hany Emile, Eric Matamoros, Arun Nagarajan, Raul J Rosenthal, Steven D Wexner.

BACKGROUND: Obesity and its associated lifestyle are known risk factors for early-onset colorectal cancer and are associated with poor postoperative and survival outcomes in older patients. We aimed to investigate the impact of obesity on the outcomes of early-onset colorectal cancers.
METHODS: Retrospective review of all patients undergoing primary resection of colon or rectal adenocarcinoma at our institution between 2015-2022. Patients who had palliative resections, resections performed at another institution, appendiceal tumors, and were underweight were excluded. The primary endpoint was survival according to the patient's body mass index: normal weight (18-24.9 kg/m2), overweight (25-29.9 kg/m2), and obesity (≥30 kg/m2). Patient and tumor characteristics and survival were compared between the three groups.
RESULTS: A total of 279 patients aged <50 years with colorectal cancer were treated at our hospital; 120 were excluded from the analysis for the following reasons: main treatment or primary resection performed at another hospital (n = 97), no resection/palliative resection (n = 23), or body mass index <18 kg/m2 (n = 2). Of these, 157 patients were included in the analysis; 61 (38.9%) were overweight and 45 (28.7%) had obesity. Except for a higher frequency of hypertension in the overweight (P = .062) and obese (P = .001) groups, no differences in patient or tumor characteristics were observed. Mean overall survival was 89 months with normal weight, 92 months with overweight, and 65 months with obesity (P = .032). Mean cancer-specific survival was 95 months with normal weight, 94 months with overweight, and 68 months with obesity (P = .018). No statistically significant difference in disease-free survival (75 vs 70 vs 59 months, P = .844) was seen.
CONCLUSION: Individuals with early-onset colorectal cancer who are overweight or obese present with similar tumor characteristics and postoperative morbidity to patients with normal weight. However, obesity may have a detrimental impact on their survival. Addressing obesity as a modifiable risk factor might improve early-onset colorectal cancer prognosis.

DOI: https://doi.org/10.1016/j.surg.2024.03.037
Cureus. 2024 Apr;16(4): e58553

Exploring the Impact of Personalized Nutritional Approaches on Metabolism and Immunity: A Systematic Review of Various Nutrients and Dietary Patterns.

Christian N Paulsingh, Muhammad Faisal Riaz, Gourav Garg, Lotanna Umeano, Sadaf Iftikhar, Sarah F Alhaddad, Pousette Hamid.

  The systematic review investigates the impact of different nutrients and dietary patterns on metabolism and immunity to answer the research question: "Can personalized nutritional approaches boost immunity?" The importance of diet in supporting the immune system has come to light in today's environment, where a strong immune system is crucial for protection against infectious illnesses, as highlighted by the COVID-19 pandemic. This systematic review adhered to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020. Four databases were screened for relevant data published in 2022-2023: PubMed, PubMed Central (PMC), MEDLINE, and Cochrane Library. Inclusion and exclusion criteria were utilized, and 13 papers were finalized after screening and employing the quality appraisal tool Cochrane Bias assessment for randomized controlled trials (RCT). Personalized nutrition can strengthen immunity and enhance overall health by adjusting dietary recommendations and following a person's genetic makeup, lifestyle, and health state. An adequate supply of vitamins, minerals, proteins, and fatty acids as well as an optimum caloric intake are essential for immune health, and individual requirements can vary significantly due to genetic factors, lifestyle choices, and underlying health conditions. Personalized nutrition considers these factors, enabling tailored dietary recommendations to address specific nutrient needs and optimize nutrient intake, leading to better health outcomes. The review concludes that personalized nutrition is more effective than a one-size-fits-all approach in boosting immunity, and its potential impact on health and immune function is highly important.

Keywords:  diet; digestion; immune function; immunity; immunometabolism; macronutrients; micronutrients; nutrition; nutrition and metabolism

DOI:  https://doi.org/10.7759/cureus.58553
Metabolites. 2024 May 10. pii: 279. [Epub ahead of print]14(5):

Mass Spectrometric Analysis of Purine Intermediary Metabolism Indicates Cyanide Induces Purine Catabolism in Rabbits.

Jordan Morningstar, Jangwoen Lee, Sari Mahon, Matthew Brenner, Anjali K Nath.

  Purines are the building blocks of DNA/RNA, energy substrates, and cofactors. Purine metabolites, including ATP, GTP, NADH, and coenzyme A, are essential molecules in diverse biological processes such as energy metabolism, signal transduction, and enzyme activity. When purine levels increase, excess purines are either recycled to synthesize purine metabolites or catabolized to the end product uric acid. Purine catabolism increases during states of low oxygen tension (hypoxia and ischemia), but this metabolic pathway is incompletely understood in the context of histotoxic hypoxia (i.e., inhibition of oxygen utilization despite normal oxygen tension). In rabbits exposed to cyanide-a classical histotoxic hypoxia agent-we demonstrated significant increases in several concordant metabolites in the purine catabolic pathway (including plasma levels of uric acid, xanthosine, xanthine, hypoxanthine, and inosine) via mass spectrometry-based metabolite profiling. Pharmacological inhibition of the purine catabolic pathway with oxypurinol mitigated the deleterious effects of cyanide on skeletal muscle cytochrome c oxidase redox state, measured by non-invasive diffuse optical spectroscopy. Finally, plasma uric acid levels correlated strongly with those of lactic acid, an established clinical biomarker of cyanide exposure, in addition to a tissue biomarker of cyanide exposure (skeletal muscle cytochrome c oxidase redox state). Cumulatively, these findings not only shed light on the in vivo role(s) of cyanide but also have implications in the field of medical countermeasure (MCM) development.

Keywords:  allopurinol; biomarker; cyanide; cytochrome c oxidase (Complex IV); histotoxic hypoxia; mass spectrometry; nucleoside/nucleotide metabolism; preclinical animal model; purine; uric acid

DOI:  https://doi.org/10.3390/metabo14050279
Metabolites. 2024 Apr 25. pii: 246. [Epub ahead of print]14(5):

Direct Infusion Mass Spectrometry to Rapidly Map Metabolic Flux of Substrates Labeled with Stable Isotopes.

Nils W F Meijer, Susan Zwakenberg, Johan Gerrits, Denise Westland, Arif I Ardisasmita, Sabine A Fuchs, Nanda M Verhoeven-Duif, Judith J M Jans, Fried J T Zwartkruis.

  Direct infusion-high-resolution mass spectrometry (DI-HRMS) allows for rapid profiling of complex mixtures of metabolites in blood, cerebrospinal fluid, tissue samples and cultured cells. Here, we present a DI-HRMS method suitable for the rapid determination of metabolic fluxes of isotopically labeled substrates in cultured cells and organoids. We adapted an automated annotation pipeline by selecting labeled adducts that best represent the majority of 13C and/or 15N-labeled glycolytic and tricarboxylic acid cycle intermediates as well as a number of their derivatives. Furthermore, valine, leucine and several of their degradation products were included. We show that DI-HRMS can determine anticipated and unanticipated alterations in metabolic fluxes along these pathways that result from the genetic alteration of single metabolic enzymes, including pyruvate dehydrogenase (PDHA1) and glutaminase (GLS). In addition, it can precisely pinpoint metabolic adaptations to the loss of methylmalonyl-CoA mutase in patient-derived liver organoids. Our results highlight the power of DI-HRMS in combination with stable isotopically labeled compounds as an efficient screening method for fluxomics.

Keywords:  TCA cycle; direct infusion–high-resolution mass spectrometry; glutaminolysis; glycolysis; isotope tracing; organoids; patient material

DOI:  https://doi.org/10.3390/metabo14050246
EMBO J. 2024 May 21.

Origins of cancer: ain't it just mature cells misbehaving?

Charles J Cho, Jeffrey W Brown, Jason C Mills.

  A pervasive view is that undifferentiated stem cells are alone responsible for generating all other cells and are the origins of cancer. However, emerging evidence demonstrates fully differentiated cells are plastic, can be coaxed to proliferate, and also play essential roles in tissue maintenance, regeneration, and tumorigenesis. Here, we review the mechanisms governing how differentiated cells become cancer cells. First, we examine the unique characteristics of differentiated cell division, focusing on why differentiated cells are more susceptible than stem cells to accumulating mutations. Next, we investigate why the evolution of multicellularity in animals likely required plastic differentiated cells that maintain the capacity to return to the cell cycle and required the tumor suppressor p53. Finally, we examine an example of an evolutionarily conserved program for the plasticity of differentiated cells, paligenosis, which helps explain the origins of cancers that arise in adults. Altogether, we highlight new perspectives for understanding the development of cancer and new strategies for preventing carcinogenic cellular transformations from occurring.

Keywords:  Differentiation; Multicellularity; Plasticity; Stem Cell; p53

DOI:  https://doi.org/10.1038/s44318-024-00099-0
Heliyon. 2024 May 30. 10(10): e30781

Different lactate metabolism subtypes reveal heterogeneity in clinical outcomes and immunotherapy in lung adenocarcinoma patients.

Jing Zhang, Yun Bao, Yang Li, Xin Shi, Xiangyu Su, Xuejun He.

   Background: The excessive accumulation of lactate within the tumor microenvironment (TME) has been demonstrated to facilitate tumor advancement and evade the immune system. Nonetheless, the metabolic status of lactate in lung adenocarcinoma (LUAD) remains uncertain.
Method: By analyzing the transcriptome profile of patients with LUAD, we created a lactate metabolism score (LMS) to predict survival. We then conducted a comprehensive examination of the biological functions and immune infiltration among different LMS patient groups. Moreover, we assessed the LMS predictive efficacy in chemotherapy and immunotherapy. Finally, we validated the detrimental phenotypic effects of SLC16A3 on LUAD cell lines (PC9 and A549) through in vitro experiments. We collected clinical samples to assess the prognostic impact of SLC16A3.
Results: We constructed an LMS model with 6 lactate metabolism regulatory factors using LASSO regression. The high LMS model indicates worse clinical outcomes for LUAD patients. High LMS patients are associated with metabolic dysregulation and increased infiltration of M0 and M1 macrophages. Low LMS patients are related to upregulated citric acid metabolism pathways and memory immune cells. High LMS patients are suitable for traditional chemotherapy, while patients with low LMS are more likely to benefit from immunotherapy. Lastly, downregulating SLC16A3 significantly reduces the proliferative and invasive capabilities of LUAD cell lines. Clinical cohort shows that patients with high expression of SLC16A3 have a worse prognosis.
Conclusions: The LMS model constructed based on the lactate metabolism pathway displays high effectiveness in predicting the outcome of patients with LUAD. LMS can offer direction regarding chemotherapy as well as immunotherapy in LUAD.

Keywords:  Drug resistance; Immune microenvironment; Lactate metabolism; Lung adenocarcinoma (LUAD); SLC16A3

DOI:  https://doi.org/10.1016/j.heliyon.2024.e30781
Adv Healthc Mater. 2024 May 22. e2400203

Fluorescence-Guided Spatial Drug Screening in 3D Colorectal Cancer Spheroids.

Jia Ning Nicolette Yau, Thirumal Yempala, Ram Pravin Kumar Muthuramalingam, Giulio Giustarini, Germaine Teng, Wee Han Ang, Dan Gibson, Giulia Adriani, Giorgia Pastorin.

  The limited recapitulation of critical cancer features in two-dimensional (2D) cultures causes poor translatability of preclinical results from in vitro assays to in vivo tumor models. This contributes to slow drug development with a low success rate. Three-dimensional (3D) cultures better recapitulate the tumor microenvironment, enabling more accurate predictions when screening drug candidates and improving the development of chemotherapeutics. Platinum (Pt) (IV) compounds are promising prodrugs designed to reduce the severe systemic toxicity of widely-used Food and Drug Administration (FDA)-approved Pt(II) drugs such as cisplatin. Here, we present spatiotemporal evaluations in 3D colorectal cancer (CRC) spheroids of mitochondria-targeting Pt(IV) complexes. CRC spheroids provide a greater pathophysiological recapitulation of in vivo tumors than 2D cultures by a marked upregulation of the ABCG2 chemoresistance marker expression. Furthermore, we introduce new 3D-staining protocols to evaluate the real-time decrease in mitochondria membrane potential (ΔΨ) in CRC spheroids, and a Pt-sensing dye to quantify the Pt mitochondrial accumulation. Finally, we demonstrate a correlation between in vitro results and the efficacy of the compounds in vivo. Overall, the CRC spheroids represent a fast and cost-effective model to assess the behavior of Pt compounds in vitro and predict their translational potential in CRC treatment. This article is protected by copyright. All rights reserved.

Keywords:  3d culture; colorectal cancer; platinum anti‐cancer drugs; platinum‐sensing dye; spheroids

DOI:  https://doi.org/10.1002/adhm.202400203
Neurobiol Learn Mem. 2024 May 19. pii: S1074-7427(24)00049-2. [Epub ahead of print]212 107938

Excision of the endothelial blood-brain barrier insulin receptor does not alter spatial cognition in mice fed either a chow or high-fat diet.

Joanne M Gladding, Neda Rafiei, Caitlin S Mitchell, Denovan P Begg.

  Insulin is transported across the blood-brain barrier (BBB) endothelium to regulate aspects of metabolism and cognition. Brain insulin resistance often results from high-fat diet (HFD) consumption and is thought to contribute to spatial cognition deficits. To target BBB insulin function, we used Cre-LoxP genetic excision of the insulin receptor (InsR) from endothelial cells in adult male mice. We hypothesized that this excision would impair spatial cognition, and that high-fat diet consumption would exacerbate these effects. Excision of the endothelial InsR did not impair performance in two spatial cognition tasks, the Y-Maze and Morris Water Maze, in tests held both before and after 14 weeks of access to high-fat (or chow control) diet. The HFD increased body weight gain and induced glucose intolerance but did not impair spatial cognition. Endothelial InsR excision tended to increase body weight and reduce sensitivity to peripheral insulin, but these metabolic effects were not associated with impairments to spatial cognition and did not interact with HFD exposure. Instead, all mice showed intact spatial cognitive performance regardless of whether they had been fed chow or a HFD, and whether the InsR had been excised or not. Overall, the results indicate that loss of the endothelial InsR does not impact spatial cognition, which is in line with pharmacological evidence that other mechanisms at the BBB facilitate insulin transport and allow it to exert its pro-cognitive effects.

Keywords:  Blood–brain barrier; High-fat diet; Insulin; Spatial cognition

DOI:  https://doi.org/10.1016/j.nlm.2024.107938
Cancer Res. 2024 May 22.

Physical Activity Decreases Inflammation and Delays Development of Obesity-Associated Pancreatic Ductal Adenocarcinoma.

Valentina Pita-Grisanti, Ericka Vélez-Bonet, Kaylin Chasser, Zachary Hurst, Alexus Liette, Grace Vulic, Kelly Dubay, Ali Lahooti, Niharika Badi, Olivia Ueltschi, Kristyn Gumpper-Fedus, Hsiang-Yin Hsueh, Ila Lahooti, Myrriah Chavez-Tomar, Samantha Terhorst, Sue E Knoblaugh, Lei Cao, Wei Huang, Christopher C Coss, Thomas A Mace, Fouad Choueiry, Alice Hinton, Stacey Culp, Jennifer M Mitchell, Rosemarie Schmandt, Michaela Onstad Grinsfelder, Karen Basen-Engquist, Zobeida Cruz-Monserrate.

Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with limited preventive strategies. Lifestyle interventions to decrease obesity represent a potential approach to prevent obesity-associated PDAC. Here, we examined whether decreasing obesity through physical activity (PA) and/or dietary changes could decrease inflammation in humans and prevent obesity-associated PDAC in mice. Comparison of circulating inflammatory-associated cytokines in subjects (overweight and obese) before and after a PA intervention revealed PA lowered systemic inflammatory cytokines. Mice with pancreatic-specific inducible KrasG12D expression were exposed to PA and/or dietary interventions during and after obesity-associated cancer initiation. In mice with concurrent diet-induced obesity (DIO) and KrasG12D expression, the PA intervention led to lower weight gain, suppressed systemic inflammation, delayed tumor progression, and decreased pro-inflammatory signals in the adipose tissue. However, these benefits were not as evident when obesity preceded pancreatic KrasG12D expression. Combining PA with diet-induced weight loss (DI-WL) delayed obesity-associated PDAC progression in the genetically engineered mouse model, but neither PA alone nor combined with DI-WL or chemotherapy prevented PDAC tumor growth in orthotopic PDAC models regardless of obesity status. PA led to upregulation of IL-15ra in adipose tissue. Adipose-specific overexpression of IL-15 slowed PDAC growth but only in non-obese mice. Overall, our study suggests that PA alone or combined with DI-WL can reduce inflammation and delay obesity-associated PDAC development or progression. Lifestyle interventions that prevent or manage obesity or therapies that target weight loss-related molecular pathways could prevent progression of PDAC.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-1045
iScience. 2024 Jun 21. 27(6): 109853

VDAC1-interacting molecules promote cell death in cancer organoids through mitochondrial-dependent metabolic interference.

Stefano Conti Nibali, Silvia De Siervi, Enrico Luchinat, Andrea Magrì, Angela Messina, Lorenza Brocca, Stefania Mantovani, Barbara Oliviero, Mario U Mondelli, Vito De Pinto, Cristian Turato, Cristina Arrigoni, Marco Lolicato.

  The voltage-dependent anion-selective channel isoform 1 (VDAC1) is a pivotal component in cellular metabolism and apoptosis with a prominent role in many cancer types, offering a unique therapeutic intervention point. Through an in-silico-to-in-vitro approach we identified a set of VA molecules (VDAC Antagonists) that selectively bind to VDAC1 and display specificity toward cancer cells. Biochemical characterization showed that VA molecules can directly interact with VDAC1 with micromolar affinity by competing with the endogenous ligand NADH for a partially shared binding site. NADH displacement results in mitochondrial distress and reduced cell proliferation, especially when compared to non-cancerous cells. Experiments performed on organoids derived from intrahepatic cholangiocarcinoma patients demonstrated a dose-dependent reduction in cell viability upon treatment with VA molecules with lower impact on healthy cells than conventional treatments like gemcitabine. VA molecules are chemical entities representing promising candidates for further optimization and development as cancer therapy strategies through precise metabolic interventions.

Keywords:  Functional aspects of cell biology; Molecular medicine; Small molecule

DOI:  https://doi.org/10.1016/j.isci.2024.109853
iScience. 2024 Jun 21. 27(6): 109817

Enzymatic depletion of circulating glutamine is immunosuppressive in cancers.

Monish Kumar, Ankita Leekha, Suman Nandy, Rohan Kulkarni, Melisa Martinez-Paniagua, K M Samiur Rahman Sefat, Richard C Willson, Navin Varadarajan.

  Although glutamine addiction in cancer cells is extensively reported, there is controversy on the impact of glutamine metabolism on the immune cells within the tumor microenvironment (TME). To address the role of extracellular glutamine, we enzymatically depleted circulating glutamine using PEGylated Helicobacter pylori gamma-glutamyl transferase (PEG-GGT) in syngeneic mouse models of breast and colon cancers. PEG-GGT treatment inhibits growth of cancer cells in vitro, but in vivo it increases myeloid-derived suppressor cells (MDSCs) and has no significant impact on tumor growth. By deriving a glutamine depletion signature, we analyze diverse human cancers within the TCGA and illustrate that glutamine depletion is not associated with favorable clinical outcomes and correlates with accumulation of MDSC. Broadly, our results help clarify the integrated impact of glutamine depletion within the TME and advance PEG-GGT as an enzymatic tool for the systemic and selective depletion (no asparaginase activity) of circulating glutamine in live animals.

Keywords:  Cancer; Immunity; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2024.109817
Commun Biol. 2024 May 20. 7(1): 608

Targeting glutamine metabolism improves sarcoma response to radiation therapy in vivo.

Rutulkumar Patel, Daniel E Cooper, Kushal T Kadakia, Annamarie Allen, Likun Duan, Lixia Luo, Nerissa T Williams, Xiaojing Liu, Jason W Locasale, David G Kirsch.

Diverse tumor metabolic phenotypes are influenced by the environment and genetic lesions. Whether these phenotypes extend to rhabdomyosarcoma (RMS) and how they might be leveraged to design new therapeutic approaches remains an open question. Thus, we utilized a Pax7Cre-ER-T2/+; NrasLSL-G12D/+; p53fl/fl (P7NP) murine model of sarcoma with mutations that most frequently occur in human embryonal RMS. To study metabolism, we infuse 13C-labeled glucose or glutamine into mice with sarcomas and show that sarcomas consume more glucose and glutamine than healthy muscle tissue. However, we reveal a marked shift from glucose consumption to glutamine metabolism after radiation therapy (RT). In addition, we show that inhibiting glutamine, either through genetic deletion of glutaminase (Gls1) or through pharmacological inhibition of glutaminase, leads to significant radiosensitization in vivo. This causes a significant increase in overall survival for mice with Gls1-deficient compared to Gls1-proficient sarcomas. Finally, Gls1-deficient sarcomas post-RT elevate levels of proteins involved in natural killer cell and interferon alpha/gamma responses, suggesting a possible role of innate immunity in the radiosensitization of Gls1-deficient sarcomas. Thus, our results indicate that glutamine contributes to radiation response in a mouse model of RMS.

DOI: https://doi.org/10.1038/s42003-024-06262-x
Clin Nutr ESPEN. 2024 Jun;pii: S2405-4577(24)00095-0. [Epub ahead of print]61 322-332

The efficacy of omega-3 fatty acids (O3FAs) as a complementary in colorectal cancer patients: A systematic review and meta-analysis.

Agung Ary Wibowo, Nathan Aditya Willyanto.

   BACKGROUND & AIMS: Colorectal cancer (CRC) is the third most common malignancy in developed countries. Therefore, omega-3 fatty acids (O3FAs) have been suggested as a beneficial complementary treatment due to their ability to regulate inflammatory responses and improve nutrition levels.This study aimed to evaluate the effects of O3FAs as a complementary treatment for inflammation, nutrition levels, post-operative infectious complications, and enhancement of recovery in CRC patients.
METHODS: The literature search was carried out through three databases. The outcomes of interest were assessed by measuring pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and CRP levels, serum albumin levels for nutrition assessment, post-operative infectious complications, and length of stay for recovery evaluation. Quality appraisal and meta-analysis were performed using RoB 2.0 and RevMan 5.4, respectively.
RESULTS: The result showed that O3FAs significantly reduced IL-6, CRP, and TNF-α, but did not affect IL-1β. Furthermore, the variable slightly increased serum albumin levels and the supplementation led to a decrease in post-operative infectious complications and shortened hospital stays.
CONCLUSION: O3FAs as a complementary treatment provided advantages for CRC patients, Further clinical trials and experiments should also be made emphasizing the impact and clinical implementation of O3FA in the nutritional status of CRC patients.

Keywords:  Colorectal cancer; Inflammation; Omega-3 fatty acids; Post-operative complications; Recovery

DOI:  https://doi.org/10.1016/j.clnesp.2024.04.002
Am J Physiol Cell Physiol. 2024 May 20.

Exogenous Ketone Esters as a Potential Therapeutic for Treatment of Sarcopenic Obesity.

Sarah E Deemer, Brandon M Roberts, Daniel Larry Smith, Eric P Plaisance, Andy Philp.

  Identifying effective treatment(s) for sarcopenia and sarcopenic obesity are of paramount importance as the global population advances in age and obesity continues to be a worldwide concern. Evidence has shown that a ketogenic diet can be beneficial for preservation of muscle quality and function in older adults, but long-term adherence is low due in part to the high-fat (> 80%), very low carbohydrate (< 5%) composition of the diet. When provided in adequate amounts, exogenous ketone esters can increase circulating ketones to concentrations that exceed those observed during prolonged fasting or starvation without significant alterations in the diet. Ketone esters first emerged in the mid-1990s and their use in pre-clinical and clinical research has escalated within the past 10-15 years. We present findings from a narrative review of the existing literature for a proposed hypothesis on the effects of exogenous ketones as a therapeutic for preservation of skeletal muscle and function within the context of sarcopenic obesity and future directions for exploration. Much of the reviewed literature herein examines the mechanisms of the ketone diester (R, S-1,3-butanediol diacetoacetate) on skeletal muscle mass, muscle protein synthesis, and epigenetic regulation in murine models. Additional studies are needed to further examine the key regulatory factors producing these effects in skeletal muscle, examine convergent and divergent effects among different ketone ester formulations, and establish optimal frequency and dosing regimens to translate these findings into humans.

Keywords:  aging; ketone diester; ketone monoester; obesity; sarcopenia

DOI:  https://doi.org/10.1152/ajpcell.00471.2023
World J Gastrointest Oncol. 2024 May 15. 16(5): 1995-2005

Casual associations between blood metabolites and colon cancer.

Ke-Yue Hu, Yi-Quan Cheng, Zhi-Long Shi, Fu-Peng Ren, Gang-Feng Xiao.

   BACKGROUND: Limited knowledge exists regarding the casual associations linking blood metabolites and the risk of developing colorectal cancer.
AIM: To investigate causal associations between blood metabolites and colon cancer.
METHODS: The study utilized a two-sample Mendelian randomization (MR) analysis to investigate the causal impact of 486 blood metabolites on colorectal cancer. The primary method of analysis used was the inverse variance weighted model. To further validate the results several sensitivity analyses were performed, including Cochran's Q test, MR-Egger intercept test, and MR robust adjusted profile score. These additional analyses were conducted to ensure the reliability and robustness of the findings.
RESULTS: After rigorous selection for genetic variation, 486 blood metabolites were included in the MR analysis. We found Mannose [odds ratio (OR) = 2.09 (1.10-3.97), P = 0.024], N-acetylglycine [OR = 3.14 (1.78-5.53), P = 7.54 × 10-8], X-11593-O-methylascorbate [OR = 1.68 (1.04-2.72), P = 0.034], 1-arachidonoylglycerophosphocholine [OR = 4.23 (2.51-7.12), P = 6.35 × 10-8] and 1-arachidonoylglycerophosphoethanolamine 4 [OR = 3.99 (1.17-13.54), P = 0.027] were positively causally associated with colorectal cancer, and we also found a negative causal relationship between Tyrosine [OR = 0.08 (0.01-0.63), P = 0.014], Urate [OR = 0.25 (0.10-0.62), P = 0.003], N-acetylglycine [0.73 (0.54-0.98), P = 0.033], X-12092 [OR = 0.89 (0.81-0.99), P = 0.028], Succinylcarnitine [OR = 0.48 (0.27-0.84), P = 0.09] with colorectal cancer. A series of sensitivity analyses were performed to confirm the rigidity of the results.
CONCLUSION: This study showed a causal relationship between 10 blood metabolites and colorectal cancer, of which 5 blood metabolites were found to be causal for the development of colorectal cancer and were confirmed as risk factors. The other five blood metabolites are protective factors.

Keywords:  Casual; Colon cancer; Genome-wide association studies; Mendelian randomization; Metabolites

DOI:  https://doi.org/10.4251/wjgo.v16.i5.1995
Genes (Basel). 2024 May 20. pii: 648. [Epub ahead of print]15(5):

Metformin as an Enhancer for the Treatment of Chemoresistant CD34+ Acute Myeloid Leukemia Cells.

Indre Krastinaite, Sergej Charkavliuk, Ruta Navakauskiene, Veronika Viktorija Borutinskaite.

  Acute myeloid leukemia is the second most frequent type of leukemia in adults. Due to a high risk of development of chemoresistance to first-line chemotherapy, the survival rate of patients in a 5-year period is below 30%. One of the reasons is that the AML population is heterogeneous, with cell populations partly composed of very primitive CD34+CD38- hematopoietic stem/progenitor cells, which are often resistant to chemotherapy. First-line treatment with cytarabine and idarubicin fails to inhibit the proliferation of CD34+CD38- cells. In this study, we investigated Metformin's effect with or without first-line conventional chemotherapy, or with other drugs like venetoclax and S63845, on primitive and undifferentiated CD34+ AML cells in order to explore the potential of Metformin or S63845 to serve as adjuvant therapy for AML. We found that first-line conventional chemotherapy treatment inhibited the growth of cells and arrested the cells in the S phase of the cell cycle; however, metformin affected the accumulation of cells in the G2/M phase. We observed that CD34+ KG1a cells respond better to lower doses of cytarabine or idarubicin in combination with metformin. Also, we determined that treatment with cytarabine, venetoclax, and S63845 downregulated the strong tendency of CD34+ KG1a cells to form cell aggregates in culture due to the downregulation of leukemic stem cell markers like CD34 and CD44, as well as adhesion markers. Also, we found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells. Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies.

Keywords:  KG-1a; S63845; cell surface markers; cytarabine; idarubicin; leukemia stem cells; metformin; venetoclax

DOI:  https://doi.org/10.3390/genes15050648