bims-medica 2024-01-14 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–01–14
33 papers selected by
Brett Chrest, East Carolina University

Ketone ester supplementation of Atkins-type diet prolongs survival in an orthotopic xenograft model of glioblastoma.
The nonessential amino acid cysteine is required to prevent ferroptosis in acute myeloid leukemia.
The Combined Treatment with Ketogenic Diet and Metformin Slows Tumor Growth in Two Mouse Models of Triple Negative Breast Cancer.
Risks of the ketogenic diet in CKD - the con part.
Glycolytic enzymes in non-glycolytic web: functional analysis of the key players.
Take metabolic heterogeneity into consideration when applying dietary interventions to cancer therapy: A review.
Ketone Bodies in Cell Physiology and Cancer.
The role of serum acylcarnitine profiling for the detection of multiple solid tumors in humans.
Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS-010759.
The determinants of metabolic discrepancies in aerobic glycolysis: Providing potential targets for breast cancer treatment.
Ketone bodies as chemical signals for the immune system.
Ferroptosis, Metabolic Rewiring, and Endometrial Cancer.
Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases.
Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.
Colon Cancer Cells Evade Drug Action by Enhancing Drug Metabolism.
Amino Acid Profiles in the Biological Fluids and Tumor Tissue of CRC Patients.
Peroxisomal β-oxidation enzyme, DECR2, regulates lipid metabolism and promotes treatment resistance in advanced prostate cancer.
Evolutionary dynamics of glucose-deprived cancer cells: insights from experimentally informed mathematical modelling.
Post-translational modulation of cell signalling through protein succinylation.
Discovery of novel brain permeable human ACSS2 inhibitors for blocking breast cancer brain metastatic growth.
Isocitrate Dehydrogenase Mutations in Cancer: Mechanisms of Transformation and Metabolic Liability.
Accessory subunit NDUFB4 participates in mitochondrial complex I supercomplex formation.
Hitting the Sweet Spot: How Glucose Metabolism Is Orchestrated in Space and Time by Phosphofructokinase-1.
Venetoclax and Hypomethylating Agent Combination in Myeloid Malignancies: Mechanisms of Synergy and Challenges of Resistance.
Paracrine signalling by pancreatic δ cells determines the glycaemic set point in mice.
Sex differences in a mouse model of diet-induced obesity: the role of the gut microbiome.
Deciphering cellular plasticity in pancreatic cancer for effective treatments.
Recreating metabolic interactions of the tumour microenvironment.
Impact of Fasting on Patients With Cancer: An Integrative Review.
GLUT-1DS resistant to ketogenic diet: from clinical feature to in silico analysis. An exemplificative case report with a literature review.
Hypoxia and intra-complex genetic suppressors rescue complex I mutants by a shared mechanism.
Monitoring the Intracellular pH and Metabolic State of Cancer Cells in Response to Chemotherapy Using a Combination of Phosphorescence Lifetime Imaging Microscopy and Fluorescence Lifetime Imaging Microscopy.
Dietary insulin indices and low-carbohydrate diet and the odds of colorectal cancer: a case-control study.

Anat Cell Biol. 2024 Jan 09.

Ketone ester supplementation of Atkins-type diet prolongs survival in an orthotopic xenograft model of glioblastoma.

Hassan Azari, Angela Poff, Dominic D'Agostino, Brent Reynolds.

  Heavy reliance on glucose metabolism and a reduced capacity to use ketone bodies makes glioblastoma (GBM) a promising candidate for ketone-based therapies. Ketogenic diet (KD) is well-known for its promising effects in controlling tumor growth in GBM. Moreover, synthetic ketone ester (KE) has demonstrated to increase blood ketone levels and enhance animal survival in a metastatic VM-M3 murine tumor model. Here, we compared the efficacy of a KE-supplemented Atkins-type diet (ATD-KE) to a classic KD in controlling tumor progression and enhancing survival in a clinically relevant orthotopic patient-derived xenograft GBM model. Our findings demonstrate that ATD-KE preserves body weight (percent change from the baseline; 112±2.99 vs. 116.9±2.52 and 104.8±3.67), decreases blood glucose (80.55±0.86 vs. 118.6±9.51 and 52.35±3.89 mg/dl), and increases ketone bodies in blood (1.15±0.03 mM vs. 0.55±0.04 and 2.66±0.21 mM) and brain tumor tissue (3.35±0.30 mM vs. 2.04±0.3 and 4.25±0.25 mM) comparable to the KD (results presented for ATD-KE vs. standard diet [STD] and KD, respectively). Importantly, the ATD-KE treatment significantly enhanced survival compared to the STD and was indistinguishable from the KD (47 days in STD vs. 56 days in KD and ATD-KE), suggesting that a nutritionally balanced low carbohydrate ATD combined with KE may be as effective as the KD alone in reducing brain tumor progression. Overall, these data support the rationale for clinical testing of KE-supplemented low-carb diet as an adjunct treatment for brain tumor patients.

Keywords:  Glioblastoma; Ketone bodies; Ketone ester; Survival; Tumor progression

DOI:  https://doi.org/10.5115/acb.23.158
Blood Adv. 2024 Jan 09. 8(1): 56-69

The nonessential amino acid cysteine is required to prevent ferroptosis in acute myeloid leukemia.

Alan Cunningham, Lieve L Oudejans, Marjan Geugien, Diego Antonio Pereira-Martins, Albertus T J Wierenga, Ayşegül Erdem, Dominique Sternadt, Gerwin Huls, Jan Jacob Schuringa.

ABSTRACT: Cysteine is a nonessential amino acid required for protein synthesis, the generation of the antioxidant glutathione, and for synthesizing the nonproteinogenic amino acid taurine. Here, we highlight the broad sensitivity of leukemic stem and progenitor cells to cysteine depletion. By CRISPR/CRISPR-associated protein 9-mediated knockout of cystathionine-γ-lyase, the cystathionine-to-cysteine converting enzyme, and by metabolite supplementation studies upstream of cysteine, we functionally prove that cysteine is not synthesized from methionine in acute myeloid leukemia (AML) cells. Therefore, although perhaps nutritionally nonessential, cysteine must be imported for survival of these specific cell types. Depletion of cyst(e)ine increased reactive oxygen species (ROS) levels, and cell death was induced predominantly as a consequence of glutathione deprivation. nicotinamide adenine dinucleotide phosphate hydrogen oxidase inhibition strongly rescued viability after cysteine depletion, highlighting this as an important source of ROS in AML. ROS-induced cell death was mediated via ferroptosis, and inhibition of glutathione peroxidase 4 (GPX4), which functions in reducing lipid peroxides, was also highly toxic. We therefore propose that GPX4 is likely key in mediating the antioxidant activity of glutathione. In line, inhibition of the ROS scavenger thioredoxin reductase with auranofin also impaired cell viability, whereby we find that oxidative phosphorylation-driven AML subtypes, in particular, are highly dependent on thioredoxin-mediated protection against ferroptosis. Although inhibition of the cystine-glutamine antiporter by sulfasalazine was ineffective as a monotherapy, its combination with L-buthionine-sulfoximine (BSO) further improved AML ferroptosis induction. We propose the combination of either sulfasalazine or antioxidant machinery inhibitors along with ROS inducers such as BSO or chemotherapy for further preclinical testing.

DOI: https://doi.org/10.1182/bloodadvances.2023010786
Res Sq. 2023 Dec 20. pii: rs.3.rs-3664129. [Epub ahead of print]

The Combined Treatment with Ketogenic Diet and Metformin Slows Tumor Growth in Two Mouse Models of Triple Negative Breast Cancer.

Karen Schmidt, Amber Thatcher, Albert Grobe, Linda Hicks, Haiwei Gu, Dorothy D Sears, Lesley G Ellies, Leonid Kalachev, Eugene Kroll.

BACKGROUND Many tumors contain hypoxic microenvironments caused by inefficient tumor vascularization. Hypoxic tumors have been shown to resist conventional cancer therapies. Hypoxic cancer cells rely on glucose to meet their energetic and anabolic needs to fuel uncontrolled proliferation and metastasis. This glucose dependency is linked to a metabolic shift in response to hypoxic conditions. METHODS To leverage the glucose dependency of hypoxic tumor cells, we assessed the effects of a controlled reduction in systemic glucose by combining dietary carbohydrate restriction, using a ketogenic diet, with gluconeogenesis inhibition, using metformin, on two mouse models of triple-negative breast cancer (TNBC). RESULTS We confirmed that MET - 1 breast cancer cells require abnormally high glucose concentrations to survive in a hypoxic environment in vitro. Then, we showed that, compared to a ketogenic diet or metformin alone, animals treated with the combination regimen showed significantly lower tumor burden, higher tumor latency and slower tumor growth. As a result, lowering systemic glucose by this combined dietary and pharmacologic approach improved overall survival in our mouse model by 31 days, which is approximately equivalent to 3 human years. CONCLUSION This is the first preclinical study to demonstrate that reducing systemic glucose by combining a ketogenic diet and metformin significantly inhibits tumor proliferation and increases overall survival. Our findings suggest a possible treatment for a broad range of hypoxic and glycolytic tumor types, one that can also augment existing treatment options to improve patient outcomes.

DOI: https://doi.org/10.21203/rs.3.rs-3664129/v1
Clin Kidney J. 2024 Jan;17(1): sfad274

Risks of the ketogenic diet in CKD - the con part.

Shivam Joshi, Rachel Shi, Jason Patel.

  The ketogenic diet is a very low carbohydrate diet that has received a lot of attention for its role in the treatment of type 2 diabetes and obesity. For patients with chronic kidney disease, there is limited evidence on the risks and/or benefits of this diet. However, from the limited evidence that does exist, there are several inferences that can be drawn regarding this diet for patients with kidney disease. The ketogenic diet may not be better than comparator higher carbohydrate diets over the long term. The diet also has low adherence levels in studies lasting ≥12 months. The diet's emphasis on fat, which often comes from animal fat, increases the consumption of saturated fat, which may increase the risk of heart disease. It has the potential to worsen metabolic acidosis by increasing dietary acid load and endogenous acid production through the oxidation of fatty acids. In addition, the diet has been associated with an increased risk of kidney stones in patients using it for the treatment of refractory epilepsy. For these reasons, and for the lack of safety data on it, it is reasonable for patients with kidney disease to avoid utilizing the ketogenic diet as a first-line option given alternative dietary patterns (like the plant-dominant diet) with less theoretical risk for harm. For those adopting the ketogenic diet in kidney disease, a plant-based version of the ketogenic diet may mitigate some of the concerns with animal-based versions of the ketogenic diet.

Keywords:  ketogenic diet; kidney disease

DOI:  https://doi.org/10.1093/ckj/sfad274
Cell Biochem Biophys. 2024 Jan 09.

Glycolytic enzymes in non-glycolytic web: functional analysis of the key players.

Avirup Malla, Suvroma Gupta, Runa Sur.

  To survive in the tumour microenvironment, cancer cells undergo rapid metabolic reprograming and adaptability. One of the key characteristics of cancer is increased glycolytic selectivity and decreased oxidative phosphorylation (OXPHOS). Apart from ATP synthesis, glycolysis is also responsible for NADH regeneration and macromolecular biosynthesis, such as amino acid biosynthesis and nucleotide biosynthesis. This allows cancer cells to survive and proliferate even in low-nutrient and oxygen conditions, making glycolytic enzymes a promising target for various anti-cancer agents. Oncogenic activation is also caused by the uncontrolled production and activity of glycolytic enzymes. Nevertheless, in addition to conventional glycolytic processes, some glycolytic enzymes are involved in non-canonical functions such as transcriptional regulation, autophagy, epigenetic changes, inflammation, various signaling cascades, redox regulation, oxidative stress, obesity and fatty acid metabolism, diabetes and neurodegenerative disorders, and hypoxia. The mechanisms underlying the non-canonical glycolytic enzyme activities are still not comprehensive. This review summarizes the current findings on the mechanisms fundamental to the non-glycolytic actions of glycolytic enzymes and their intermediates in maintaining the tumor microenvironment.

Keywords:  Cancer; Enzyme; Glycolysis; Metabolism; Non-glycolytic function; OXPHOS

DOI:  https://doi.org/10.1007/s12013-023-01213-5
Heliyon. 2023 Dec;9(12): e22814

Take metabolic heterogeneity into consideration when applying dietary interventions to cancer therapy: A review.

Chun Ni, Jian Li.

  In recent years, dietary interventions have attracted much attention in cancer therapy. Mechanistic studies suggest that dietary interventions can inhibit the progression of cancer through deprivation of essential metabolites, lowering the levels of protumor hormones, activation of anticancer immunity and synergistic effects with conventional anticancer therapies. The feasibility, safety and promising tumor outcomes have also been established in humans. However, the results from both preclinical and clinical studies are inconsistent or even conflicting, the reasons for which have not been extensively considered. In this review, we discuss the various heterogeneity, including dietary protocols, tissue of origin and cancer locations, spatial and temporal metabolic heterogeneity, and divergent combination treatment, that may affect the responses of different cancers to dietary interventions. Understanding this heterogeneity and taking them into consideration when applying dietary interventions to cancer therapy will allow us to deliver the right diet to the right patient at the right time to maximize compliance, safety and efficacy of conventional anticancer therapy and to improve the outcomes of patients with cancer.

Keywords:  Anticancer therapy; Cancer; Dietary interventions; Metabolic heterogeneity; Precision nutrition

DOI:  https://doi.org/10.1016/j.heliyon.2023.e22814
Am J Physiol Cell Physiol. 2024 Jan 08.

Ketone Bodies in Cell Physiology and Cancer.

Giacomo Giuliani, Valter D Longo.

  Ketogenic diets (KDs), fasting, or prolonged physical activity elevate serum ketone bodies (KBs) levels, providing an alternative fuel source for the brain and other organs. However, KBs play pleiotropic roles that go beyond their role in energy production. KBs can act as signaling metabolites, influence gene expression, proteins' post-translational modifications (PTMs), inflammation, and oxidative stress. Here, we explore the impact of KBs on mammalian cell physiology, including aging and tissue regeneration. We also concentrate on KBs and cancer, given the extensive evidence that dietary approaches inducing ketosis, including Fasting Mimicking Diets (FMDs) and KDs, can prevent and affect tumor progression.

Keywords:  cancer; fasting mimicking diet; ketone bodies; tumor metabolism; ß-hydroxybutyrate

DOI:  https://doi.org/10.1152/ajpcell.00441.2023
Heliyon. 2024 Jan 15. 10(1): e23867

The role of serum acylcarnitine profiling for the detection of multiple solid tumors in humans.

Longjunyu Wu, Chunhua Ye, Qingchun Yao, Qianqian Li, Chunyan Zhang, Yuandong Li.

  Metabolic reprogramming is an essential hallmark of cancer. Several studies have reported the dysregulation of acylcarnitine (ACar) metabolism in tumor cells, suggesting that changes in the blood ACar may be related to tumor growth. Accordingly, this study aimed to understand the alteration of serum ACar profiles in various solid tumors and explore the potential of differential serum ACars as diagnostic biomarkers. A series of 69 relatively abundant ACars were identified via untargeted analysis. Then, targeted metabolomics was used to describe the metabolic alterations in ACars between normal controls and patients with six types of solid tumors. The results suggested that changes in ACars correlated with their carbon chain length and saturation. The six tumor types had highly similar ACar metabolic profiles, indicating similar fatty acid oxidation (FAO) metabolic pathways. Moreover, the receiver operating curve analysis of differential ACars showed that 16 ACars (C8-C14) had high diagnostic capability towards the studied solid tumors. Specifically, the area under the curve of ACar 10:2 isomer2 and ACar 12:2 isomer2 was greater than 0.95. In conclusion, the marked decrease in the levels of medium- and long-chain ACars (C8-C18) in the six solid tumors suggests that they may have similar FAO-based metabolic pathways, which could afford a common target for cancer therapy. Additionally, 16 ACars (C8-C14) were identified as potential biomarkers for diagnosing six types of solid tumors.

Keywords:  Acylcarnitines; Fatty acid oxidation; Metabolic reprogramming; Metabolomics; Solid tumors

DOI:  https://doi.org/10.1016/j.heliyon.2023.e23867
Mol Oncol. 2024 Jan 12.

Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS-010759.

Marc Pujalte-Martin, Amine Belaïd, Simon Bost, Michel Kahi, Pascal Peraldi, Matthieu Rouleau, Nathalie M Mazure, Frédéric Bost.

  Metformin and IACS-010759 are two distinct antimetabolic agents. Metformin, an established antidiabetic drug, mildly inhibits mitochondrial complex I, while IACS-010759 is a new potent mitochondrial complex I inhibitor. Mitochondria is pivotal in the energy metabolism of cells by providing adenosine triphosphate through oxidative phosphorylation (OXPHOS). Hence, mitochondrial metabolism and OXPHOS become a vulnerability when targeted in cancer cells. Both drugs have promising antitumoral effects in diverse cancers, supported by preclinical in vitro and in vivo studies. We present evidence of their direct impact on cancer cells and their immunomodulatory effects. In clinical studies, while observational epidemiologic studies on metformin were encouraging, actual trial results were not as expected. However, IACS-01075 exhibited major adverse effects, thereby causing a metabolic shift to glycolysis and elevated lactic acid concentrations. Therefore, the future outlook for these two drugs depends on preventive clinical trials for metformin and investigations into the plausible toxic effects on normal cells for IACS-01075.

Keywords:  IACS-010759; cancer; clinical trial; immunometabolism; metformin; microenvironment

DOI:  https://doi.org/10.1002/1878-0261.13583
Biochimie. 2024 Jan 04. pii: S0300-9084(24)00003-8. [Epub ahead of print]220 107-121

The determinants of metabolic discrepancies in aerobic glycolysis: Providing potential targets for breast cancer treatment.

Ajeesh Babu Littleflower, Sulfath Thottungal Parambil, Gisha Rose Antony, Lakshmi Subhadradevi.

  Altered aerobic glycolysis is the robust mechanism to support cancer cell survival and proliferation beyond the maintenance of cellular energy metabolism. Several investigators portrayed the important role of deregulated glycolysis in different cancers, including breast cancer. Breast cancer is the most ubiquitous form of cancer and the primary cause of cancer death in women worldwide. Breast cancer with increased glycolytic flux is hampered to eradicate with current therapies and can result in tumor recurrence. In spite of the low order efficiency of ATP production, cancer cells are highly addicted to glycolysis. The glycolytic dependency of cancer cells provides potential therapeutic strategies to preferentially kill cancer cells by inhibiting glycolysis using antiglycolytic agents. The present review emphasizes the most recent research on the implication of glycolytic enzymes, including glucose transporters (GLUTs), hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), lactate dehydrogenase-A (LDHA), associated signalling pathways and transcription factors, as well as the antiglycolytic agents that target key glycolytic enzymes in breast cancer. The potential activity of glycolytic inhibitors impinges cancer prevalence and cellular resistance to conventional drugs even under worse physiological conditions such as hypoxia. As a single agent or in combination with other chemotherapeutic drugs, it provides the feasibility of new therapeutic modalities against a wide spectrum of human cancers.

Keywords:  Aerobic glycolysis; Anti-glycolytic agents; Breast cancer; Glucose metabolism; Glycolytic enzymes; Targeted therapy

DOI:  https://doi.org/10.1016/j.biochi.2024.01.003
Am J Physiol Cell Physiol. 2024 Jan 08.

Ketone bodies as chemical signals for the immune system.

Michelangelo Bauwelz Gonzatti, Emily Goldberg.

  Ketone bodies are short chain fatty acids produced by the liver during periods of limited glucose availability, such as during fasting or low carbohydrate feeding. Recent studies have highlighted important non-metabolic functions of the most abundant ketone body, β-hydroxybutyrate (BHB). Notably, many of these functions, including limiting certain sources of inflammation, histone deacetylase inhibition, NFκB inhibition, and GPCR stimulation, are particularly important to consider in immune cells. Likewise, dietary manipulations like caloric restriction or ketogenic diet feeding are associated with lowered inflammation, improved health outcomes, and improved host defense against infection, although the underlying mechanisms of the broad benefits of ketosis remain incompletely understood. In this perspective, we contextualize the current state of the field of non-metabolic functions of ketone bodies specifically in the immune system and speculate on the molecular explanations and broader physiological significance.

Keywords:  BHB; immune; inflammation; ketone bodies; metabolism

DOI:  https://doi.org/10.1152/ajpcell.00478.2023
Int J Mol Sci. 2023 Dec 20. pii: 75. [Epub ahead of print]25(1):

Ferroptosis, Metabolic Rewiring, and Endometrial Cancer.

Eglė Žalytė.

  Ferroptosis is a newly discovered form of regulated cell death. The main feature of ferroptosis is excessive membrane lipid peroxidation caused by iron-mediated chemical and enzymatic reactions. In normal cells, harmful lipid peroxides are neutralized by glutathione peroxidase 4 (GPX4). When GPX4 is inhibited, ferroptosis occurs. In mammalian cells, ferroptosis serves as a tumor suppression mechanism. Not surprisingly, in recent years, ferroptosis induction has gained attention as a potential anticancer strategy, alone or in combination with other conventional therapies. However, sensitivity to ferroptosis inducers depends on the metabolic state of the cell. Endometrial cancer (EC) is the sixth most common cancer in the world, with more than 66,000 new cases diagnosed every year. Out of all gynecological cancers, carcinogenesis of EC is mostly dependent on metabolic abnormalities. Changes in the uptake and catabolism of iron, lipids, glucose, and glutamine affect the redox capacity of EC cells and, consequently, their sensitivity to ferroptosis-inducing agents. In addition to this, in EC cells, ferroptosis-related genes are usually mutated and overexpressed, which makes ferroptosis a promising target for EC prediction, diagnosis, and therapy. However, for a successful application of ferroptosis, the connection between metabolic rewiring and ferroptosis in EC needs to be deciphered, which is the focus of this review.

Keywords:  endometrial cancer; ferroptosis; metabolism; resistance

DOI:  https://doi.org/10.3390/ijms25010075
Int J Mol Sci. 2023 Dec 21. pii: 124. [Epub ahead of print]25(1):

Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases.

Jiwon Jang, Su Rim Kim, Jo Eun Lee, Seoyeon Lee, Hyeong Jig Son, Wonchae Choe, Kyung-Sik Yoon, Sung Soo Kim, Eui-Ju Yeo, Insug Kang.

  Ketone bodies (KBs), such as acetoacetate and β-hydroxybutyrate, serve as crucial alternative energy sources during glucose deficiency. KBs, generated through ketogenesis in the liver, are metabolized into acetyl-CoA in extrahepatic tissues, entering the tricarboxylic acid cycle and electron transport chain for ATP production. Reduced glucose metabolism and mitochondrial dysfunction correlate with increased neuronal death and brain damage during cerebral ischemia and neurodegeneration. Both KBs and the ketogenic diet (KD) demonstrate neuroprotective effects by orchestrating various cellular processes through metabolic and signaling functions. They enhance mitochondrial function, mitigate oxidative stress and apoptosis, and regulate epigenetic and post-translational modifications of histones and non-histone proteins. Additionally, KBs and KD contribute to reducing neuroinflammation and modulating autophagy, neurotransmission systems, and gut microbiome. This review aims to explore the current understanding of the molecular mechanisms underpinning the neuroprotective effects of KBs and KD against brain damage in cerebral ischemia and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.

Keywords:  Alzheimer’s disease; Parkinson’s disease; cerebral ischemia; ketogenic diet; ketone bodies; mitochondrial dysfunction; neurodegenerative disease; neuroinflammation; oxidative stress; β-hydroxybutyrate

DOI:  https://doi.org/10.3390/ijms25010124
bioRxiv. 2023 Dec 24. pii: 2023.12.24.573250. [Epub ahead of print]

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 C 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.

DOI: https://doi.org/10.1101/2023.12.24.573250
bioRxiv. 2023 Dec 23. pii: 2023.12.21.572817. [Epub ahead of print]

Colon Cancer Cells Evade Drug Action by Enhancing Drug Metabolism.

Bojie Cong, Teena Thakur, Alejandro Huerta Uribe, Evangelia Stamou, Sindhura Gopinath, Oliver Maddocks, Ross Cagan.

Colorectal cancer (CRC) is the second most deadly cancer worldwide. One key reason is the failure of therapies that target RAS proteins, which represent approximately 40% of CRC cases. Despite the recent discovery of multiple alternative signalling pathways that contribute to resistance, durable therapies remain an unmet need. Here, we use liquid chromatography/mass spectrometry (LC/MS) analyses on Drosophila CRC tumour models to identify multiple metabolites in the glucuronidation pathway-a toxin clearance pathway-as upregulated in trametinib-resistant RAS/APC/P53 ("RAP") tumours compared to trametinib-sensitive RASG12V tumours. Elevating glucuronidation was sufficient to direct trametinib resistance in RASG12V animals while, conversely, inhibiting different steps along the glucuronidation pathway strongly reversed RAP resistance to trametinib. For example, blocking an initial HDAC1-mediated deacetylation step with the FDA-approved drug vorinostat strongly suppressed trametinib resistance in Drosophila RAP tumours. We provide functional evidence that pairing oncogenic RAS with hyperactive WNT activity strongly elevates PI3K/AKT/GLUT signalling, which in turn directs elevated glucose and subsequent glucuronidation. Finally, we show that this mechanism of trametinib resistance is conserved in an KRAS/APC/TP53 mouse CRC tumour organoid model. Our observations demonstrate a key mechanism by which oncogenic RAS/WNT activity promotes increased drug clearance in CRC. The majority of targeted therapies are glucuronidated, and our results provide a specific path towards abrogating this resistance in clinical trials.

DOI: https://doi.org/10.1101/2023.12.21.572817
Cancers (Basel). 2023 Dec 22. pii: 69. [Epub ahead of print]16(1):

Amino Acid Profiles in the Biological Fluids and Tumor Tissue of CRC Patients.

Marisa Domingues Santos, Ivo Barros, Pedro Brandão, Lúcia Lacerda.

  Amino acids are the building blocks of proteins and essential players in pathways such as the citric acid and urea cycle, purine and pyrimidine biosynthesis, and redox cell signaling. Therefore, it is unsurprising that these molecules have a significant role in cancer metabolism and its metabolic plasticity. As one of the most prevalent malign diseases, colorectal cancer needs biomarkers for its early detection, prognostic, and prediction of response to therapy. However, the available biomarkers for this disease must be more powerful and present several drawbacks, such as high costs and complex laboratory procedures. Metabolomics has gathered substantial attention in the past two decades as a screening platform to study new metabolites, partly due to the development of techniques, such as mass spectrometry or liquid chromatography, which have become standard practice in diagnostic procedures for other diseases. Extensive metabolomic studies have been performed in colorectal cancer (CRC) patients in the past years, and several exciting results concerning amino acid metabolism have been found. This review aims to gather and present findings concerning alterations in the amino acid plasma pool of colorectal cancer patients.

Keywords:  amino acids; biomarkers; colorectal cancer; diagnosis; laboratorial findings; metabolomics; prognosis; treatment response

DOI:  https://doi.org/10.3390/cancers16010069
Br J Cancer. 2024 Jan 12.

Peroxisomal β-oxidation enzyme, DECR2, regulates lipid metabolism and promotes treatment resistance in advanced prostate cancer.

Chui Yan Mah, An Dieu Trang Nguyen, Takuto Niijima, Madison Helm, Jonas Dehairs, Feargal J Ryan, Natalie Ryan, Lake-Ee Quek, Andrew J Hoy, Anthony S Don, Ian G Mills, Johannes V Swinnen, David J Lynn, Zeyad D Nassar, Lisa M Butler.

BACKGROUND: Peroxisomes are central metabolic organelles that have key roles in fatty acid homoeostasis. As prostate cancer (PCa) is particularly reliant on fatty acid metabolism, we explored the contribution of peroxisomal β-oxidation (perFAO) to PCa viability and therapy response.
METHODS: Bioinformatic analysis was performed on clinical transcriptomic datasets to identify the perFAO enzyme, 2,4-dienoyl CoA reductase 2 (DECR2) as a target gene of interest. Impact of DECR2 and perFAO inhibition via thioridazine was examined in vitro, in vivo, and in clinical prostate tumours cultured ex vivo. Transcriptomic and lipidomic profiling was used to determine the functional consequences of DECR2 inhibition in PCa.
RESULTS: DECR2 is upregulated in clinical PCa, most notably in metastatic castrate-resistant PCa (CRPC). Depletion of DECR2 significantly suppressed proliferation, migration, and 3D growth of a range of CRPC and therapy-resistant PCa cell lines, and inhibited LNCaP tumour growth and proliferation in vivo. DECR2 influences cell cycle progression and lipid metabolism to support tumour cell proliferation. Further, co-targeting of perFAO and standard-of-care androgen receptor inhibition enhanced suppression of PCa cell proliferation.
CONCLUSION: Our findings support a focus on perFAO, specifically DECR2, as a promising therapeutic target for CRPC and as a novel strategy to overcome lethal treatment resistance.

DOI: https://doi.org/10.1038/s41416-023-02557-8
J R Soc Interface. 2024 Jan;21(210): 20230587

Evolutionary dynamics of glucose-deprived cancer cells: insights from experimentally informed mathematical modelling.

Luis Almeida, Jérôme Alexandre Denis, Nathalie Ferrand, Tommaso Lorenzi, Antonin Prunet, Michéle Sabbah, Chiara Villa.

  Glucose is a primary energy source for cancer cells. Several lines of evidence support the idea that monocarboxylate transporters, such as MCT1, elicit metabolic reprogramming of cancer cells in glucose-poor environments, allowing them to re-use lactate, a by-product of glucose metabolism, as an alternative energy source with serious consequences for disease progression. We employ a synergistic experimental and mathematical modelling approach to explore the evolutionary processes at the root of cancer cell adaptation to glucose deprivation, with particular focus on the mechanisms underlying the increase in MCT1 expression observed in glucose-deprived aggressive cancer cells. Data from in vitro experiments on breast cancer cells are used to inform and calibrate a mathematical model that comprises a partial integro-differential equation for the dynamics of a population of cancer cells structured by the level of MCT1 expression. Analytical and numerical results of this model suggest that environment-induced changes in MCT1 expression mediated by lactate-associated signalling pathways enable a prompt adaptive response of glucose-deprived cancer cells, while fluctuations in MCT1 expression due to epigenetic changes create the substrate for environmental selection to act upon, speeding up the selective sweep underlying cancer cell adaptation to glucose deprivation, and may constitute a long-term bet-hedging mechanism.

Keywords:  MCT1 expression; breast cancer; evolutionary dynamics; mathematical modelling; metabolic reprogramming; phenotype-structured equations

DOI:  https://doi.org/10.1098/rsif.2023.0587
Explor Target Antitumor Ther. 2023 ;4(6): 1260-1285

Post-translational modulation of cell signalling through protein succinylation.

Katharina F Kubatzky, Yue Gao, Dayoung Yu.

  Cells need to adapt their activities to extra- and intracellular signalling cues. To translate a received extracellular signal, cells have specific receptors that transmit the signal to downstream proteins so that it can reach the nucleus to initiate or repress gene transcription. Post-translational modifications (PTMs) of proteins are reversible or irreversible chemical modifications that help to further modulate protein activity. The most commonly observed PTMs are the phosphorylation of serine, threonine, and tyrosine residues, followed by acetylation, glycosylation, and amidation. In addition to PTMs that involve the modification of a certain amino acid (phosphorylation, hydrophobic groups for membrane localisation, or chemical groups like acylation), or the conjugation of peptides (SUMOylation, NEDDylation), structural changes such as the formation of disulphide bridge, protein cleavage or splicing can also be classified as PTMs. Recently, it was discovered that metabolites from the tricarboxylic acid (TCA) cycle are not only intermediates that support cellular metabolism but can also modify lysine residues. This has been shown for acetate, succinate, and lactate, among others. Due to the importance of mitochondria for the overall fitness of organisms, the regulatory function of such PTMs is critical for protection from aging, neurodegeneration, or cardiovascular disease. Cancer cells and activated immune cells display a phenotype of accelerated metabolic activity known as the Warburg effect. This metabolic state is characterised by enhanced glycolysis, the use of the pentose phosphate pathway as well as a disruption of the TCA cycle, ultimately causing the accumulation of metabolites like citrate, succinate, and malate. Succinate can then serve as a signalling molecule by directly interacting with proteins, by binding to its G protein-coupled receptor 91 (GPR91) and by post-translationally modifying proteins through succinylation of lysine residues, respectively. This review is focus on the process of protein succinylation and its importance in health and disease.

Keywords:  Succinate; cancer; immune system; lysine succinylation; metabolites; mitochondria; post-translational modifications

DOI:  https://doi.org/10.37349/etat.2023.00196
bioRxiv. 2023 Dec 23. pii: 2023.12.22.573073. [Epub ahead of print]

Discovery of novel brain permeable human ACSS2 inhibitors for blocking breast cancer brain metastatic growth.

Emily Esquea, Lorela Ciraku, Riley G Young, Jessica Merzy, Alexandra N Talarico, Adel Ahmed Rashad, Simon Cocklin, Nicole L Simone, Joris Beld, Mauricio J Reginato, Alexej Dick.

Breast-cancer brain metastasis (BCBM) poses a significant clinical challenge, resulting in an end-stage diagnosis and hindered by limited therapeutic options. The blood-brain barrier (BBB) acts as an anatomical and physiological hurdle for therapeutic compounds, restricting the effective delivery of therapies to the brain. In order to grow and survive in a nutrient-poor environment, tumors in the brain must adapt to their metabolic needs, becoming highly dependent on acetate. These tumors rely on the conversion of acetate to acetyl-CoA by the enzyme Acetyl-CoA synthetase 2 (ACSS2), a key metabolic enzyme involved in regulating fatty acid synthesis and protein acetylation in tumor cells. ACSS2 has emerged as a crucial enzyme required for the growth of tumors in the brain. Here, we utilized a computational pipeline, combining pharmacophore-based shape screen methodology with ADME property predictions to identify novel brain-permeable ACSS2 inhibitors. From a small molecule library, this approach identified 30 potential ACSS2 binders, from which two candidates, AD-5584 and AD-8007, were validated for their binding affinity, predicted metabolic stability, and, notably, their ability to traverse the BBB. We show that treatment of BCBM cells, MDA-MB-231BR, with AD-5584 and AD-8007 leads to a significant reduction in lipid storage, reduction in colony formation, and increase in cell death in vitro . Utilizing an ex vivo orthotopic brain-slice tumor model, we show that treatment with AD-8007 and AD-5584 significantly reduces tumor size and synergizes with radiation in blocking BCBM tumor growth ex vivo. Importantly, we show that following intraperitoneal injections with AD-5584 and AD-8007, we can detect these compounds in the brain, confirming their BBB permeability. Thus, we have identified and validated novel ACSS2 inhibitor candidates for further drug development and optimization as agents for treating patients with breast cancer brain metastasis.

DOI: https://doi.org/10.1101/2023.12.22.573073
Cold Spring Harb Perspect Med. 2024 Jan 08. pii: a041537. [Epub ahead of print]

Isocitrate Dehydrogenase Mutations in Cancer: Mechanisms of Transformation and Metabolic Liability.

Kathryn Gunn, Julie-Aurore Losman.

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are metabolic enzymes that interconvert isocitrate and 2-oxoglutarate (2OG). Gain-of-function mutations in IDH1 and IDH2 occur in a number of cancers, including acute myeloid leukemia, glioma, cholangiocarcinoma, and chondrosarcoma. These mutations cripple the wild-type activity of IDH and cause the enzymes to catalyze a partial reverse reaction in which 2OG is reduced but not carboxylated, resulting in production of the (R)-enantiomer of 2-hydroxyglutarate ((R)-2HG). (R)-2HG accumulation in IDH-mutant tumors results in profound dysregulation of cellular metabolism. The most well-characterized oncogenic effects of (R)-2HG involve the dysregulation of 2OG-dependent epigenetic tumor-suppressor enzymes. However, (R)-2HG has many other effects in IDH-mutant cells, some that promote transformation and others that induce metabolic dependencies. Herein, we review how cancer-associated IDH mutations impact epigenetic regulation and cellular metabolism and discuss how these effects can potentially be leveraged to therapeutically target IDH-mutant tumors.

DOI: https://doi.org/10.1101/cshperspect.a041537
J Biol Chem. 2024 Jan 08. pii: S0021-9258(24)00002-4. [Epub ahead of print] 105626

Accessory subunit NDUFB4 participates in mitochondrial complex I supercomplex formation.

Gaganvir Parmar, Claire Fong-McMaster, Chantal Pileggi, David A Patten, Alexanne Cuillerier, Stephanie Myers, Ying Wang, Siegfried Hekimi, Miroslava Cuperlovic-Culf, Mary-Ellen Harper.

  Mitochondrial electron transport chain (ETC) complexes organize into supramolecular structures called respiratory supercomplexes (SCs). The role of respiratory SC remains largely unconfirmed despite evidence supporting their necessity for mitochondrial respiratory function. The mechanisms underlying the formation of the I1III2IV1 "respirasome" SC are also not fully understood, further limiting insights into these processes in physiology and diseases, including neurodegeneration and metabolic syndromes. NDUFB4 is a complex I accessory subunit that contains residues that interact with the subunit UQCRC1 from complex III, suggesting that NDUFB4 is integral for I1III2IV1 respirasome integrity. Here, we introduced specific point mutations to Asn24 (N24) and Arg30 (R30) residues on NDUFB4 to decipher the role of I1III2-containing respiratory SCs in cellular metabolism while minimizing the functional consequences to complex I assembly. Our results demonstrate that NDUFB4 point mutations N24A and R30A impair I1III2IV1 respirasome assembly and reduce mitochondrial respiratory flux. Steady-state metabolomics also revealed a global decrease in TCA cycle metabolites, affecting NADH-generating substrates. Taken together, our findings highlight an integral role of NDUFB4 in respirasome assembly and demonstrate the functional significance of SCs in regulating mammalian cell bioenergetics.

Keywords:  Mitochondria; NDUFB4; electron transport chain; oxidative phosphorylation; respirasome; steady-state metabolomics; supercomplexes

DOI:  https://doi.org/10.1016/j.jbc.2024.105626
Cancers (Basel). 2023 Dec 19. pii: 16. [Epub ahead of print]16(1):

Hitting the Sweet Spot: How Glucose Metabolism Is Orchestrated in Space and Time by Phosphofructokinase-1.

Melissa Campos, Lauren V Albrecht.

  Glycolysis is the central metabolic pathway across all kingdoms of life. Intensive research efforts have been devoted to understanding the tightly orchestrated processes of converting glucose into energy in health and disease. Our review highlights the advances in knowledge of how metabolic and gene networks are integrated through the precise spatiotemporal compartmentalization of rate-limiting enzymes. We provide an overview of technically innovative approaches that have been applied to study phosphofructokinase-1 (PFK1), which represents the fate-determining step of oxidative glucose metabolism. Specifically, we discuss fast-acting chemical biology and optogenetic tools that have delineated new links between metabolite fluxes and transcriptional reprogramming, which operate together to enact tissue-specific processes. Finally, we discuss how recent paradigm-shifting insights into the fundamental basis of glycolytic regulatory control have shed light on the mechanisms of tumorigenesis and could provide insight into new therapeutic vulnerabilities in cancer.

Keywords:  cancer; compartmentalization; condensate; glucosome; glycolysis; localization; optogenetics; phosphofructokinase-1; spatiotemporal; subcellular

DOI:  https://doi.org/10.3390/cancers16010016
Int J Mol Sci. 2023 Dec 29. pii: 484. [Epub ahead of print]25(1):

Venetoclax and Hypomethylating Agent Combination in Myeloid Malignancies: Mechanisms of Synergy and Challenges of Resistance.

Rahul Mishra, Maedeh Zokaei Nikoo, Sindhusha Veeraballi, Abhay Singh.

  There has been a widespread adoption of hypomethylating agents (HMA: 5-Azacytidine (5-Aza)/decitabine) and venetoclax (Ven) for the treatment of acute myeloid leukemia (AML); however, the mechanisms behind the combination's synergy are poorly understood. Monotherapy often encounters resistance, leading to suboptimal outcomes; however, the combination of HMA and Ven has demonstrated substantial improvements in treatment responses. This study elucidates multiple synergistic pathways contributing to this enhanced therapeutic effect. Key mechanisms include HMA-mediated downregulation of anti-apoptotic proteins, notably MCL-1, and the priming of cells for Ven through the induction of genes encoding pro-apoptotic proteins such as Noxa. Moreover, Ven induces sensitization to HMA, induces overcoming resistance by inhibiting the DHODH enzyme, and disrupts antioxidant pathways (Nrf2) induced by HMA. The combination further disrupts oxidative phosphorylation in leukemia stem cells, amplifying the therapeutic impact. Remarkably, clinical studies have revealed a favorable response, particularly in patients harboring specific mutations, such as IDH1/2, NPM1, CEBPA, or ASXL1. This prompts future studies to explore the nuanced underpinnings of these synergistic mechanisms in AML patients with these molecular signatures.

Keywords:  Venetoclax-5-Azacytidine; acute myeloid leukemia; hypomethylating agents; myeloid malignancies

DOI:  https://doi.org/10.3390/ijms25010484
Nat Metab. 2024 Jan 09.

Paracrine signalling by pancreatic δ cells determines the glycaemic set point in mice.

Jessica L Huang, Mohammad S Pourhosseinzadeh, Sharon Lee, Niels Krämer, Jaresley V Guillen, Naomi H Cinque, Paola Aniceto, Ariana T Momen, Shinichiro Koike, Mark O Huising.

While pancreatic β and α cells are considered the main drivers of blood glucose homeostasis through insulin and glucagon secretion, the contribution of δ cells and somatostatin (SST) secretion to glucose homeostasis remains unresolved. Here we provide a quantitative assessment of the physiological contribution of δ cells to the glycaemic set point in mice. Employing three orthogonal mouse models to remove SST signalling within the pancreas or transplanted islets, we demonstrate that ablating δ cells or SST leads to a sustained decrease in the glycaemic set point. This reduction coincides with a decreased glucose threshold for insulin response from β cells, leading to increased insulin secretion to the same glucose challenge. Our data demonstrate that β cells are sufficient to maintain stable glycaemia and reveal that the physiological role of δ cells is to provide tonic feedback inhibition that reduces the β cell glucose threshold and consequently lowers the glycaemic set point in vivo.

DOI: https://doi.org/10.1038/s42255-023-00944-2
Biol Sex Differ. 2024 Jan 10. 15(1): 5

Sex differences in a mouse model of diet-induced obesity: the role of the gut microbiome.

Saluda Stapleton, Grace Welch, Lindsay DiBerardo, Linnea R Freeman.

   BACKGROUND: Recent decades have seen an exponential rise in global obesity prevalence, with rates nearly doubling in a span of 40 years. A comprehensive knowledge base regarding the systemic effects of obesity is required to create new preventative and therapeutic agents effective at combating the current obesity epidemic. Previous studies of diet-induced obesity utilizing mouse models have demonstrated a difference in bodyweight gain by sex. In such studies, female mice gained significantly less weight than male mice when given the same high fat (HF) diet, indicating a resistance to diet-induced obesity. Research has also shown sex differences in gut microbiome composition between males and females, indicated to be in part a result of sex hormones. Understanding metabolic differences between sexes could assist in the development of new measures for obesity prevention and treatment. This study aimed to characterize sex differences in weight gain, plasma lipid profiles, fecal microbiota composition, and fecal short chain fatty acid levels. We hypothesized a role for the gut microbiome in these sex differences that would be normalized following microbiome depletion.
METHODS: A mouse model was used to study these effects. Mice were divided into treatment groups by sex, diet, and presence/absence of an antibiotic cocktail to deplete genera in the gut microbiome. We hypothesized that sex differences would be present both in bodyweight gain and systemic measures of obesity, including hormone and circulating free fatty acid levels.
RESULTS: We determined statistically significant differences for sex and/or treatment for the outcome measures. We confirm previous findings in which male mice gained significantly more weight than female mice fed the same high fat diet. However, sex differences persisted following antibiotic administration for microbiome depletion.
CONCLUSIONS: We conclude that sex differences in the gut microbiome may contribute to sex differences in obesity, but they do not explain all of the differences.

Keywords:  Diet-induced obesity; Gut microbiome; Metabolic profile; Sex differences; Short chain fatty acids

DOI:  https://doi.org/10.1186/s13293-023-00580-1
Cancer Metastasis Rev. 2024 Jan 09.

Deciphering cellular plasticity in pancreatic cancer for effective treatments.

Md Hafiz Uddin, Dingqiang Zhang, Irfana Muqbil, Bassel F El-Rayes, Herbert Chen, Philip A Philip, Asfar S Azmi.

  Cellular plasticity and therapy resistance are critical features of pancreatic cancer, a highly aggressive and fatal disease. The pancreas, a vital organ that produces digestive enzymes and hormones, is often affected by two main types of cancer: the pre-dominant ductal adenocarcinoma and the less common neuroendocrine tumors. These cancers are difficult to treat due to their complex biology characterized by cellular plasticity leading to therapy resistance. Cellular plasticity refers to the capability of cancer cells to change and adapt to different microenvironments within the body which includes acinar-ductal metaplasia, epithelial to mesenchymal/epigenetic/metabolic plasticity, as well as stemness. This plasticity allows heterogeneity of cancer cells, metastasis, and evasion of host's immune system and develops resistance to radiation, chemotherapy, and targeted therapy. To overcome this resistance, extensive research is ongoing exploring the intrinsic and extrinsic factors through cellular reprogramming, chemosensitization, targeting metabolic, key survival pathways, etc. In this review, we discussed the mechanisms of cellular plasticity involving cellular adaptation and tumor microenvironment and provided a comprehensive understanding of its role in therapy resistance and ways to overcome it.

Keywords:  Cellular plasticity; Pancreatic cancer; Stemness; Therapy resistance

DOI:  https://doi.org/10.1007/s10555-023-10164-5
Trends Endocrinol Metab. 2024 Jan 10. pii: S1043-2760(23)00250-3. [Epub ahead of print]

Recreating metabolic interactions of the tumour microenvironment.

Rodrigo Curvello, Nikolaus Berndt, Sandra Hauser, Daniela Loessner.

  Tumours are heterogeneous tissues containing diverse populations of cells and an abundant extracellular matrix (ECM). This tumour microenvironment prompts cancer cells to adapt their metabolism to survive and grow. Besides epigenetic factors, the metabolism of cancer cells is shaped by crosstalk with stromal cells and extracellular components. To date, most experimental models neglect the complexity of the tumour microenvironment and its relevance in regulating the dynamics of the metabolism in cancer. We discuss emerging strategies to model cellular and extracellular aspects of cancer metabolism. We highlight cancer models based on bioengineering, animal, and mathematical approaches to recreate cell-cell and cell-matrix interactions and patient-specific metabolism. Combining these approaches will improve our understanding of cancer metabolism and support the development of metabolism-targeting therapies.

Keywords:  cancer metabolism; cancer models; mathematical models; tumour microenvironment

DOI:  https://doi.org/10.1016/j.tem.2023.12.005
J Adv Pract Oncol. 2023 Nov;14(7): 608-619

Impact of Fasting on Patients With Cancer: An Integrative Review.

Samantha Thompson, Lydia T Madsen, Angela Bazzell.

Background: Patients with cancer often pursue nutrition as an avenue to positively impact their care management and disease outcomes. Nutritional interventions are increasing in popularity, especially intermittent fasting as an adjunct to chemotherapy. However, limited research is available on the impact of intermittent fasting on patients with cancer.
Methods: A comprehensive literature search was conducted using Ovid MEDLINE, Ovid EMBASE, and CINAHL databases.
Results: 514 articles were identified from the three databases. Seven studies remained after applying inclusion and exclusion criteria. The seven studies included in this review examined fasting compliance, malnutrition, therapy side effects, endocrine parameters, quality of life measures, and cancer outcomes. Data suggest overall good compliance, no malnutrition, minimal side effects, a trend toward improved endocrine parameters, unchanged quality of life (QOL), and mixed results for cancer outcomes.
Conclusion: Intermittent fasting as an adjunct to chemotherapy in normal-weight patients with cancer has potential as a safe, tolerable, and feasible nutritional intervention that could positively impact treatment outcomes and QOL. Large-scale randomized controlled trials are needed to validate these findings and determine what future role intermittent fasting may play in cancer management.

DOI: https://doi.org/10.6004/jadpro.2023.14.7.5
Neurogenetics. 2024 Jan 08.

GLUT-1DS resistant to ketogenic diet: from clinical feature to in silico analysis. An exemplificative case report with a literature review.

Raffaele Falsaperla, Vincenzo Sortino, Giovanna Vitaliti, Grete Francesca Privitera, Martino Ruggieri, Gaia Fusto, Xena Giada Pappalardo.

  Glucose transporter type 1 deficiency syndrome (GLUT-1DS) is characterized by alterations in glucose translocation through the blood-brain barrier (BBB) due to mutation involving the GLUT-1 transporter. The fundamental therapy is ketogenic diet (KD) that provide an alternative energetic substrate - ketone bodies that across the BBB via MCT-1 - for the brain. Symptoms are various and include intractable seizure, acquired microcephalia, abnormal ocular movement, movement disorder, and neurodevelopment delay secondary to an energetic crisis for persistent neuroglycopenia. KD is extremely effective in controlling epileptic seizures and has a positive impact on movement disorders and cognitive impairment. Cases of KD resistance are rare, and only a few of them are reported in the literature, all regarding seizure. Our study describes a peculiar case of GLUT-1DS due to a new deletion involving the first codon of SLC2A1 gene determining a loss of function with a resistance to KD admitted to hospital due to intractable episodes of dystonia. This patient presented a worsening of symptomatology at higher ketonemia values but without hyperketosis and showed a complete resolution of symptomatology while maintaining low ketonemia values. Our study proposes an in-silico genomic and proteomic analysis aimed at explaining the atypical response to KD exhibited by our patient. In this way, we propose a new clinical and research approach based on precision medicine and molecular modelling to be applied to patients with GLUT-1DS resistant to first-line treatment with ketogenic diet by in silico study of genetic and altered protein product.

Keywords:  GLUT1-DS; In silico analysis; Ketogenic diet; Movement disorder; Resistant

DOI:  https://doi.org/10.1007/s10048-023-00742-8
Cell. 2024 Jan 05. pii: S0092-8674(23)01342-9. [Epub ahead of print]

Hypoxia and intra-complex genetic suppressors rescue complex I mutants by a shared mechanism.

Joshua D Meisel, Maria Miranda, Owen S Skinner, Presli P Wiesenthal, Sandra M Wellner, Alexis A Jourdain, Gary Ruvkun, Vamsi K Mootha.

  The electron transport chain (ETC) of mitochondria, bacteria, and archaea couples electron flow to proton pumping and is adapted to diverse oxygen environments. Remarkably, in mice, neurological disease due to ETC complex I dysfunction is rescued by hypoxia through unknown mechanisms. Here, we show that hypoxia rescue and hyperoxia sensitivity of complex I deficiency are evolutionarily conserved to C. elegans and are specific to mutants that compromise the electron-conducting matrix arm. We show that hypoxia rescue does not involve the hypoxia-inducible factor pathway or attenuation of reactive oxygen species. To discover the mechanism, we use C. elegans genetic screens to identify suppressor mutations in the complex I accessory subunit NDUFA6/nuo-3 that phenocopy hypoxia rescue. We show that NDUFA6/nuo-3(G60D) or hypoxia directly restores complex I forward activity, with downstream rescue of ETC flux and, in some cases, complex I levels. Additional screens identify residues within the ubiquinone binding pocket as being required for the rescue by NDUFA6/nuo-3(G60D) or hypoxia. This reveals oxygen-sensitive coupling between an accessory subunit and the quinone binding pocket of complex I that can restore forward activity in the same manner as hypoxia.

Keywords:  C. elegans; NADH:ubiquinone oxidoreductase; NDUFA6; NDUFS4; complex I; electron transport chain; hyperoxia; hypoxia; mitochondria; oxygen

DOI:  https://doi.org/10.1016/j.cell.2023.12.010
Int J Mol Sci. 2023 Dec 19. pii: 49. [Epub ahead of print]25(1):

Monitoring the Intracellular pH and Metabolic State of Cancer Cells in Response to Chemotherapy Using a Combination of Phosphorescence Lifetime Imaging Microscopy and Fluorescence Lifetime Imaging Microscopy.

Irina Druzhkova, Anastasiya Komarova, Elena Nikonova, Vadim Baigildin, Artem Mozherov, Yuliya Shakirova, Uliana Lisitsa, Vladislav Shcheslavskiy, Nadezhda Ignatova, Evgeny Shirshin, Marina Shirmanova, Sergey Tunik.

  The extracellular matrix (ECM), in which collagen is the most abundant protein, impacts many aspects of tumor physiology, including cellular metabolism and intracellular pH (pHi), as well as the efficacy of chemotherapy. Meanwhile, the role of collagen in differential cell responses to treatment within heterogeneous tumor environments remains poorly investigated. In the present study, we simultaneously monitored the changes in pHi and metabolism in living colorectal cancer cells in vitro upon treatment with a chemotherapeutic combination, FOLFOX (5-fluorouracil, oxaliplatin and leucovorin). The pHi was followed using the new pH-sensitive probe BC-Ga-Ir, working in the mode of phosphorescence lifetime imaging (PLIM), and metabolism was assessed from the autofluorescence of the metabolic cofactor NAD(P)H using fluorescence lifetime imaging (FLIM) with a two-photon laser scanning microscope. To model the ECM, 3D collagen-based hydrogels were used, and comparisons with conventional monolayer cells were made. It was found that FOLFOX treatment caused an early temporal intracellular acidification (reduction in pHi), followed by a shift to more alkaline values, and changed cellular metabolism to a more oxidative state. The presence of unstructured collagen markedly reduced the cytotoxic effects of FOLFOX, and delayed and diminished the pHi and metabolic responses. These results support the observation that collagen is a factor in the heterogeneous response of cancer cells to chemotherapy and a powerful regulator of their metabolic behavior.

Keywords:  FLIM; FOLFOX; HCT116 cell line; PLIM; collagen; intracellular pH; metabolism

DOI:  https://doi.org/10.3390/ijms25010049
Eur J Cancer Prev. 2023 Dec 18.

Dietary insulin indices and low-carbohydrate diet and the odds of colorectal cancer: a case-control study.

Alireza Bahrami, Karim Parastouei, Maryam Taghdir, Mojtaba Ghadyani.

BACKGROUND: Regarding the role of insulin and insulin-inducing dietary factors in some cancers' etiology, we hypothesized that the risk of colorectal cancer may be lessened by following a lower carbohydrate and insulinogenic diet. Therefore, we performed this study to explore the association between a low-carbohydrate diet and insulin indices and the odds of colorectal cancer.
METHOD: This hospital-based case-control study was conducted on 150 newly diagnosed colorectal cancer patients and 300 healthy age- and sex-matched hospitalized controls. A valid and reliable food frequency questionnaire was used to calculate the insulin indices and low-carbohydrate diet score. Multivariate logistic regression was used to estimate the association between insulin indices and low-carbohydrate diet and the odds of colorectal cancer.
RESULT: After adjusting for potential confounders, individuals in the highest tertile of insulin indices had a higher risk of colorectal cancer (ORinsulin index = 3.46; 95% CI, 2.00-5.96; ORinsulin load = 2; 95% CI, 1.17-3.41). No association was found between a low-carbohydrate diet and colorectal cancer (OR = 1.55; 95% CI, 0.85-2.84).
CONCLUSION: Current results demonstrated that a high insulinemic diet was associated with a higher risk of colorectal cancer.

DOI: https://doi.org/10.1097/CEJ.0000000000000867