bims-medica 2024-09-08 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024‒09‒08
29 papers selected by
Brett Chrest, East Carolina University

A Ketogenic Diet Sensitizes Pancreatic Cancer to Inhibition of Glutamine Metabolism.
Sex- and Age-Specific Differences in Mice Fed a Ketogenic Diet.
Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.
Pharmacological inhibition of ENT1 enhances the impact of specific dietary fats on energy metabolism gene expression.
Global 13C tracing and metabolic flux analysis of intact human liver tissue ex vivo.
Cytidine deaminase-dependent mitochondrial biogenesis as a potential vulnerability in pancreatic cancer cells.
BET inhibitors (BETi) influence oxidative phosphorylation metabolism by affecting mitochondrial dynamics leading to alterations in apoptotic pathways in triple-negative breast cancer (TNBC) cells.
Multiplex genome editing eliminates the Warburg Effect without impacting growth rate in mammalian cells.
Mitochondrial Transfer as a Strategy for Enhancing Cancer Cell Fitness:Current Insights and Future Directions.
p53 Orchestrates Cancer Metabolism: Unveiling Strategies to Reverse the Warburg Effect.
The Effects of Ketogenic Diets and Ketone Supplements on the Aerobic Performance of Endurance Runners: A Systematic Review.
Perspective: Key considerations when developing and publishing dietary interventions for human clinical trials.
Homoharringtonine sensitized resistant acute myeloid leukemia cells to venetoclax-induced apoptosis.
Glutaminase 1 plays critical roles in myelodysplastic syndrome and acute myeloid leukemia cells.
Modification in mitochondrial function is associated with the FADS1 variant and its interaction with alpha-linolenic acid-enriched diet - an exploratory study.
Exploring the Relationship Between Diet, Lifestyle and Gut Microbiome in Colorectal Cancer Development: A Recent Update.
Unraveling brain palmitic acid: Origin, levels and metabolic fate.
WT1 And DNMT3A Mutations in Prognostic Significance of Acute Myeloid Leukemia: A Meta-Analysis.
The compartment-specific manipulation of the NAD+/NADH ratio affects the metabolome and the function of glioblastoma.
Safety, Efficacy, and Predictive Factors of Venetoclax-Based Regimens in Elderly Acute Myeloid Leukemia Patients: A Meta-Analysis.
Understanding the interplay between dNTP metabolism and genome stability in cancer.
SDHAF2 facilitates mitochondrial respiration through stabilizing succinate dehydrogenase and cytochrome c oxidase assemblies.
The Clinical Impact of Time-restricted Eating on Cancer: A Systematic Review.
Ven the dose matters: Venetoclax dosing in the frontline treatment of AML.
Are there interindividual differences in the reactive hypoglycaemia response to breakfast? A replicate crossover trial.
Analysis of Unfolded Protein Response Activation in Colon Adenocarcinoma Epithelial Cells: A Proteomic Study.
Impact of Serum Ferritin and Iron Overload on Acute Myeloid Leukemia Outcomes: A Systematic Review and Meta-Analysis.
Phenylalanine deprivation inhibits multiple myeloma progression by perturbing endoplasmic reticulum homeostasis.
TRAP1 modulates mitochondrial biogenesis via PGC-1α/TFAM signalling pathway in colorectal cancer cells.

bioRxiv. 2024 Jul 23. pii: 2024.07.19.604377. [Epub ahead of print]

A Ketogenic Diet Sensitizes Pancreatic Cancer to Inhibition of Glutamine Metabolism.

Omid Hajihassani, Mehrdad Zarei, Asael Roichman, Alexander Loftus, Christina S Boutros, Jonathan Hue, Parnian Naji, Jacob Boyer, Soubhi Tahan, Peter Gallagher, William Beegan, James Choi, Shihong Lei, Christine Kim, Moeez Rathore, Faith Nakazzi, Ishan Shah, Kevin Lebo, Helen Cheng, Anusha Mudigonda, Sydney Alibeckoff, Karen Ji, Hallie Graor, Masaru Miyagi, Ali Vaziri-Gohar, Henri Brunengraber, Rui Wang, Peder J Lund, Luke D Rothermel, Joshua D Rabinowitz, Jordan M Winter.

Pancreatic cancer is the third leading cause of cancer death in the United States, and while conventional chemotherapy remains the standard treatment, responses are poor. Safe and alternative therapeutic strategies are urgently needed 1 . A ketogenic diet has been shown to have anti-tumor effects across diverse cancer types but will unlikely have a significant effect alone. However, the diet shifts metabolism in tumors to create new vulnerabilities that can be targeted (1). Modulators of glutamine metabolism have shown promise in pre-clinical models but have failed to have a marked impact against cancer in the clinic. We show that a ketogenic diet increases TCA and glutamine-associated metabolites in murine pancreatic cancer models and under metabolic conditions that simulate a ketogenic diet in vitro. The metabolic shift leads to increased reliance on glutamine-mediated anaplerosis to compensate for low glucose abundance associated with a ketogenic diet. As a result, glutamine metabolism inhibitors, such as DON and CB839 in combination with a ketogenic diet had robust anti-cancer effects. These findings provide rationale to study the use of a ketogenic diet with glutamine targeted therapies in a clinical context.

DOI: https://doi.org/10.1101/2024.07.19.604377
Nutrients. 2024 Aug 16. pii: 2731. [Epub ahead of print]16(16):

Sex- and Age-Specific Differences in Mice Fed a Ketogenic Diet.

Kenyon W Sprankle, Mya A Knappenberger, Erica J Locke, Jack H Thompson, Madison F Vinovrski, Kaylin Knapsack, Stephen C Kolwicz.

  The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that results in the elevation of serum ketone bodies, known as ketosis. This metabolic consequence has been suggested as a method for treating neurological conditions, improving exercise performance, and facilitating weight loss for overweight individuals. However, since most research primarily uses male populations, little is known about the potential sex differences during the consumption of the KD. In addition, the effects of the KD on aging are relatively unexplored. Therefore, the purpose of this study was to explore sex- and age-specific differences in mice fed the KD. Male and female C57BL/6N mice at either 12 wks or 24 wks of age were randomly assigned to a KD (90% fat, 1% carbohydrate) or chow (13% fat, 60% carbohydrate) group for 6 wks. KD induced weight gain, increased adiposity, induced hyperlipidemia, caused lipid accumulation in the heart and liver, and led to glycogen depletion in the heart, liver, and muscle with varying degrees of changes depending on age and sex. While younger and older male mice on the KD were prone to glucose intolerance, the KD acutely improved rotarod performance in younger females. Overall, this study highlights potential sex and aging differences in the adaptation to the KD.

Keywords:  glucose intolerance; ketone bodies; ketosis; lipid accumulation; metabolism

DOI:  https://doi.org/10.3390/nu16162731
J Biol Chem. 2024 Sep 03. pii: S0021-9258(24)02247-6. [Epub ahead of print] 107746

Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.

Antonio J Rua, Wayne Mitchell, Steven M Claypool, Nathan N Alder, Andrei T Alexandrescu.

  Mitochondria are central to cellular metabolism; hence, their dysfunction contributes to a wide array of human diseases. Cardiolipin, the signature phospholipid of the mitochondrion, affects proper cristae morphology, bioenergetic functions, and metabolic reactions carried out in mitochondrial membranes. To match tissue-specific metabolic demands, cardiolipin typically undergoes an acyl tail remodeling process with the final step carried out by the phospholipid-lysophospholipid transacylase tafazzin. Mutations in tafazzin are the primary cause of Barth syndrome. Here, we investigated how defects in cardiolipin biosynthesis and remodeling impacts metabolic flux through the TCA cycle and associated yeast pathways. Nuclear magnetic resonance was used to monitor in real-time the metabolic fate of 13C3-pyruvate in isolated mitochondria from three isogenic yeast strains. We compared mitochondria from a wild-type strain to mitochondria from a Δtaz1 strain that lacks tafazzin and contains lower amounts of unremodeled cardiolipin, and mitochondria from a Δcrd1 strain that lacks cardiolipin synthase and cannot synthesize cardiolipin. We found that the 13C-label from the pyruvate substrate was distributed through twelve metabolites. Several of the metabolites were specific to yeast pathways including branched chain amino acids and fusel alcohol synthesis. While most metabolites showed similar kinetics amongst the different strains, mevalonate concentrations were significantly increased in Δtaz1 mitochondria. Additionally, the kinetic profiles of α-ketoglutarate, as well as NAD+ and NADH measured in separate experiments, displayed significantly lower concentrations for Δtaz1 and Δcrd1 mitochondria at most time points. Taken together, the results show how cardiolipin remodeling influences pyruvate metabolism, tricarboxylic acid cycle flux, and the levels of mitochondrial nucleotides.

Keywords:  3-methylglutaconic acid (3MGA); Barth syndrome (BTHS); Krebs cycle; adenosine triphosphate (ATP); metabolic disease; mitochondrial respiration; nuclear magnetic resonance (NMR); tricarboxylic acid (TCA) cycle

DOI:  https://doi.org/10.1016/j.jbc.2024.107746
Proc Natl Acad Sci U S A. 2024 Sep 03. 121(36): e2321874121

Pharmacological inhibition of ENT1 enhances the impact of specific dietary fats on energy metabolism gene expression.

Erwann Pain, Stuart Snowden, Joseph Oddy, Sonia Shinhmar, Yousef M A Alhammad, Jason S King, Annette Müller-Taubenberger, Robin S B Williams.

  Medium chain fatty acids are commonly consumed as part of diets for endurance sports and as medical treatment in ketogenic diets where these diets regulate energy metabolism and increase adenosine levels. However, the role of the equilibrative nucleoside transporter 1 (ENT1), which is responsible for adenosine transport across membranes in this process, is not well understood. Here, we investigate ENT1 activity in controlling the effects of two dietary medium chain fatty acids (decanoic and octanoic acid), employing the tractable model system Dictyostelium. We show that genetic ablation of three ENT1 orthologues unexpectedly improves cell proliferation specifically following decanoic acid treatment. This effect is not caused by increased adenosine levels triggered by both fatty acids in the presence of ENT1 activity. Instead, we show that decanoic acid increases expression of energy-related genes relevant for fatty acid β-oxidation, and that pharmacological inhibition of ENT1 activity leads to an enhanced effect of decanoic acid to increase expression of tricarboxylicacid cycle and oxidative phosphorylation components. Importantly, similar transcriptional changes have been shown in the rat hippocampus during ketogenic diet treatment. We validated these changes by showing enhanced mitochondria load and reduced lipid droplets. Thus, our data show that ENT1 regulates the medium chain fatty acid-induced increase in cellular adenosine levels and the decanoic acid-induced expression of important metabolic enzymes in energy provision, identifying a key role for ENT1 proteins in metabolic effects of medium chain fatty acids.

Keywords:  Dictyostelium discoideum; decanoic acid; energy metabolism; ketogenic diets; medium chain triglycerides

DOI:  https://doi.org/10.1073/pnas.2321874121
Nat Metab. 2024 Aug 29.

Global 13C tracing and metabolic flux analysis of intact human liver tissue ex vivo.

Nina Grankvist, Cecilia Jönsson, Karin Hedin, Nicolas Sundqvist, Per Sandström, Bergthor Björnsson, Arjana Begzati, Evgeniya Mickols, Per Artursson, Mohit Jain, Gunnar Cedersund, Roland Nilsson.

Liver metabolism is central to human physiology and influences the pathogenesis of common metabolic diseases. Yet, our understanding of human liver metabolism remains incomplete, with much of current knowledge based on animal or cell culture models that do not fully recapitulate human physiology. Here, we perform in-depth measurement of metabolism in intact human liver tissue ex vivo using global 13C tracing, non-targeted mass spectrometry and model-based metabolic flux analysis. Isotope tracing allowed qualitative assessment of a wide range of metabolic pathways within a single experiment, confirming well-known features of liver metabolism but also revealing unexpected metabolic activities such as de novo creatine synthesis and branched-chain amino acid transamination, where human liver appears to differ from rodent models. Glucose production ex vivo correlated with donor plasma glucose, suggesting that cultured liver tissue retains individual metabolic phenotypes, and could be suppressed by postprandial levels of nutrients and insulin, and also by pharmacological inhibition of glycogen utilization. Isotope tracing ex vivo allows measuring human liver metabolism with great depth and resolution in an experimentally tractable system.

DOI: https://doi.org/10.1038/s42255-024-01119-3
Commun Biol. 2024 Aug 30. 7(1): 1065

Cytidine deaminase-dependent mitochondrial biogenesis as a potential vulnerability in pancreatic cancer cells.

Audrey Frances, Audrey Lumeau, Nicolas Bery, Marion Gayral, Lucille Stuani, Marie Sorbara, Estelle Saland, Delphine Pagan, Naïma Hanoun, Jérôme Torrisani, Anthony Lemarié, Jean-Charles Portais, Louis Buscail, Nelson Dusetti, Jean-Emmanuel Sarry, Pierre Cordelier.

Cytidine deaminase (CDA) converts cytidine and deoxycytidine into uridine and deoxyuridine as part of the pyrimidine salvage pathway. Elevated levels of CDA are found in pancreatic tumors and associated with chemoresistance. Recent evidence suggests that CDA has additional functions in cancer cell biology. In this work, we uncover a novel role of CDA in pancreatic cancer cell metabolism. CDA silencing impairs mitochondrial metabolite production, respiration, and ATP production in pancreatic cancer cells, leading to a so-called Pasteur effect metabolic shift towards glycolysis. Conversely, we find that CDA expression promotes mitochondrial biogenesis and oxidative phosphorylation, independently of CDA deaminase activity. Furthermore, we observe that patient primary cells overexpressing CDA are more sensitive to mitochondria-targeting drugs. Collectively, this work shows that CDA plays a non-canonical role in pancreatic cancer biology by promoting mitochondrial function, which could be translated into novel therapeutic vulnerabilities.

DOI: https://doi.org/10.1038/s42003-024-06760-y
Cell Prolif. 2024 Sep 02. e13730

BET inhibitors (BETi) influence oxidative phosphorylation metabolism by affecting mitochondrial dynamics leading to alterations in apoptotic pathways in triple-negative breast cancer (TNBC) cells.

Teresa Rossi, Egidio Iorio, Mattea Chirico, Maria Elena Pisanu, Nicola Amodio, Maria Eugenia Gallo Cantafio, Ida Perrotta, Francesca Colciaghi, Marco Fiorillo, Alessia Gianferrari, Noemi Puccio, Antonino Neri, Alessia Ciarrocchi, Mariaelena Pistoni.

Repressing BET proteins' function using bromodomain inhibitors (BETi) has been shown to elicit antitumor effects by regulating the transcription of genes downstream of BRD4. We previously showed that BETi promoted cell death of triple-negative breast cancer (TNBC) cells. Here, we proved that BETi induce altered mitochondrial dynamics fitness in TNBC cells falling in cell death. We demonstrated that BETi treatment downregulated the expression of BCL-2, and proteins involved in mitochondrial fission and increased fused mitochondria. Impaired mitochondrial fission affected oxidative phosphorylation (OXPHOS) inducing the expression of OXPHOS-related genes, SDHa and ATP5a, and increased cell death. Consistently, the amount of mitochondrial DNA and mitochondrial membrane potential (∆Ψm) increased in BETi-treated cells compared to control cells. Lastly, BETi in combination with Metformin reduced cell growth. Our results indicate that mitochondrial dynamics and OXPHOS metabolism support breast cancer proliferation and represent novel BETi downstream targets in TNBC cells.

DOI: https://doi.org/10.1111/cpr.13730
bioRxiv. 2024 Aug 06. pii: 2024.08.02.606284. [Epub ahead of print]

Multiplex genome editing eliminates the Warburg Effect without impacting growth rate in mammalian cells.

Hooman Hefzi, Iván Martínez-Monge, Igor Marin de Mas, Nicholas Luke Cowie, Alejandro Gomez Toledo, Soo Min Noh, Karen Julie la Cour Karottki, Marianne Decker, Johnny Arnsdorf, Jose Manuel Camacho-Zaragoza, Stefan Kol, Sanne Schoffelen, Nuša Pristovšek, Anders Holmgaard Hansen, Antonio A Miguez, Sara Petersen Bjorn, Karen Kathrine Brøndum, Elham Maria Javidi, Kristian Lund Jensen, Laura Stangl, Emanuel Kreidl, Thomas Beuchert Kallehauge, Daniel Ley, Patrice Ménard, Helle Munck Petersen, Zulfiya Sukhova, Anton Bauer, Emilio Casanova, Niall Barron, Johan Malmström, Lars K Nielsen, Gyun Min Lee, Helene Faustrup Kildegaard, Bjørn G Voldborg, Nathan E Lewis.

The Warburg effect is ubiquitous in proliferative mammalian cells, including cancer cells, but poses challenges for biopharmaceutical production, as lactate accumulation inhibits cell growth and protein production. Previous efforts to eliminate lactate production via knockout have failed in mammalian bioprocessing since lactate dehydrogenase has proven essential. However, here we eliminated the Warburg effect in Chinese hamster ovary (CHO) and HEK293 cells by simultaneously knocking out lactate dehydrogenase and regulators involved in a negative feedback loop that typically inhibits pyruvate conversion to acetyl-CoA. In contrast to long-standing assumptions about the role of aerobic glycolysis, Warburg-null cells maintain wildtype growth rate while producing negligible lactate. Further characterization of Warburg-null CHO cells showed a compensatory increase in oxygen consumption, a near total reliance on oxidative metabolism, and higher cell densities in fed-batch cell culture. These cells remained amenable for production of diverse biotherapeutic proteins, reaching industrially relevant titers and maintaining product glycosylation. Thus, the ability to eliminate the Warburg effect is an important development for biotherapeutic production and provides a tool for investigating a near-universal metabolic phenomenon.

DOI: https://doi.org/10.1101/2024.08.02.606284
Pharmacol Res. 2024 Aug 30. pii: S1043-6618(24)00327-X. [Epub ahead of print]208 107382

Mitochondrial Transfer as a Strategy for Enhancing Cancer Cell Fitness:Current Insights and Future Directions.

Veronica Marabitti, Elisabetta Vulpis, Francesca Nazio, Silvia Campello.

  It is now recognized that tumors are not merely masses of transformed cells but are intricately interconnected with healthy cells in the tumor microenvironment (TME), forming complex and heterogeneous structures. Recent studies discovered that cancer cells can steal mitochondria from healthy cells to empower themselves, while reducing the functions of their target organ. Mitochondrial transfer, i.e. the intercellular movement of mitochondria, is recently emerging as a novel process in cancer biology, contributing to tumor growth, metastasis, and resistance to therapy by shaping the metabolic landscape of the tumor microenvironment. This review highlights the influence of transferred mitochondria on cancer bioenergetics, redox balance and apoptotic resistance, which collectively foster aggressive cancer phenotype. Furthermore, the therapeutic implications of mitochondrial transfer are discussed, emphasizing the potential of targeting these pathways to overcome drug resistance and improve treatment efficacy.

Keywords:  Mitochondria transfer; cancer therapy; metabolic alterations; tumor microenvironment

DOI:  https://doi.org/10.1016/j.phrs.2024.107382
Bull Math Biol. 2024 Aug 29. 86(10): 124

p53 Orchestrates Cancer Metabolism: Unveiling Strategies to Reverse the Warburg Effect.

Roba Abukwaik, Elias Vera-Siguenza, Daniel Tennant, Fabian Spill.

  Cancer cells exhibit significant alterations in their metabolism, characterised by a reduction in oxidative phosphorylation (OXPHOS) and an increased reliance on glycolysis, even in the presence of oxygen. This metabolic shift, known as the Warburg effect, is pivotal in fuelling cancer's uncontrolled growth, invasion, and therapeutic resistance. While dysregulation of many genes contributes to this metabolic shift, the tumour suppressor gene p53 emerges as a master player. Yet, the molecular mechanisms remain elusive. This study introduces a comprehensive mathematical model, integrating essential p53 targets, offering insights into how p53 orchestrates its targets to redirect cancer metabolism towards an OXPHOS-dominant state. Simulation outcomes align closely with experimental data comparing glucose metabolism in colon cancer cells with wild-type and mutated p53. Additionally, our findings reveal the dynamic capability of elevated p53 activation to fully reverse the Warburg effect, highlighting the significance of its activity levels not just in triggering apoptosis (programmed cell death) post-chemotherapy but also in modifying the metabolic pathways implicated in treatment resistance. In scenarios of p53 mutations, our analysis suggests targeting glycolysis-instigating signalling pathways as an alternative strategy, whereas targeting solely synthesis of cytochrome c oxidase 2 (SCO2) does support mitochondrial respiration but may not effectively suppress the glycolysis pathway, potentially boosting the energy production and cancer cell viability.

Keywords:  Cancer metabolism; Glycolysis; Hypoxia; Mathematical biology; Warburg effect; p53

DOI:  https://doi.org/10.1007/s11538-024-01346-5
Sports Health. 2024 Sep 04. 19417381241271547

The Effects of Ketogenic Diets and Ketone Supplements on the Aerobic Performance of Endurance Runners: A Systematic Review.

Kexin Sun, Yee Tung Choi, Clare Chung Wah Yu, Edmund Anthony Severn Nelson, Jorming Goh, Siyu Dai, Lai Ling Hui.

  CONTEXT: Ketogenic diets and ketone supplements have gained popularity among endurance runners given their purported effects: potentially delaying the onset of fatigue by enabling the increased utilization of the body's fat reserve or external ketone bodies during prolonged running.OBJECTIVE: This systematic review was conducted to evaluate the effects of ketogenic diets (>60% fat and <10% carbohydrates/<50 g carbohydrates per day) or ketone supplements (ketone esters or ketone salts, medium-chain triglycerides or 1,3-butadiol) on the aerobic performance of endurance runners.
DATA SOURCES: A systematic search was conducted in PubMed, Web of Science, Pro Quest, and Science Direct for publications up to October 2023.
STUDY SELECTION: Human studies on the effects of ketogenic diets or ketone supplements on the aerobic performance of adult endurance runners were included after independent screening by 2 reviewers.
STUDY DESIGN: Systematic review.
LEVEL OF EVIDENCE: Level 3.
DATA EXTRACTION: Primary outcomes were markers of aerobic performance (maximal oxygen uptake [VO2max], race time, time to exhaustion and rate of perceived exertion).
RESULTS: VO2max was assessed by incremental test to exhaustion. Endurance performance was assessed by time trials, 180-minute running trials, or run-to-exhaustion trials; 5 studies on ketogenic diets and 7 studies on ketone supplements involving a total of 132 endurance runners were included. Despite the heterogeneity in study design and protocol, none reported benefits of ketogenic diets or ketone supplements on selected markers of aerobic performance compared with controls. Reduction in bodyweight and fat while preserving lean mass and improved glycemic control were reported in some included studies on ketogenic diets.
CONCLUSION: This review did not identify any significant advantages or disadvantages of ketogenic diets or ketone supplements for the aerobic performance of endurance runners. Further trials with larger sample sizes, more gender-balanced participants, longer ketogenic diet interventions, and follow-up on metabolic health are warranted.

Keywords:  aerobic performance; endurance runners; ketogenic diets; ketone supplements

DOI:  https://doi.org/10.1177/19417381241271547
J Nutr. 2024 Aug 30. pii: S0022-3166(24)00475-9. [Epub ahead of print]

Perspective: Key considerations when developing and publishing dietary interventions for human clinical trials.

Heather J Leidy, Rachel Gooding, Kristen Hicks-Roof.

  A key guiding principle in the 2020-2025 Dietary Guidelines for Americans emphasizes the need for individuals to choose eating habits that allows for personal, cultural, and traditional preferences while establishing a high-quality diet. This concept becomes a daunting task given the need to reduce the consumption of foods higher in saturated fat, sodium, and/or added sugar - which are typically found in familiar, highly palatable foods most-often liked and consumed in the United States. Similarly, in nutrition intervention studies, adherence to healthier dietary patterns is typically low as a result of many factors, including reduced taste, flavor, and familiarity to the study foods. Increasing evidence illustrates the promising role of herbs and spices to maintain acceptability of healthier food options for nutrition interventions. This perspective paper was informed by a Satellite Session presented at the American Society for Nutrition's annual meeting, Nutrition 2023, entitled, "Developing Culturally Appropriate Recipes for Human Clinical Trials," which explored several proposed 'best practice' guidelines when developing nutrition interventions to improve dietary adherence and acceptability within clinical trials. The session also highlighted a need to include sufficient detail concerning the types and amounts of specific foods included within nutrition interventions in combination with preparation methods and study recipes, including herbs and spices, to improve intervention reproducibility and translatability for future research, dietary guidelines, and clinical practice.

Keywords:  clinical nutrition research; clinical recipes; dietary interventions; herbs and spices; nutrition intervention guidance

DOI:  https://doi.org/10.1016/j.tjnut.2024.08.024
Leuk Lymphoma. 2024 Sep 05. 1-13

Homoharringtonine sensitized resistant acute myeloid leukemia cells to venetoclax-induced apoptosis.

Zhao Yin, Ya Gao, Xiaoyin Bu, Junhui Wang, Zurong Yao, Qifa Liu, Yu Zhang, Guopan Yu, Baohong Ping.

  Venetoclax (VEN), a B-cell lymphoma 2 (BCL-2) selective inhibitor, is widely used for treating acute myeloid leukemia (AML) with promising results. However, the anti-leukemic effect of VEN in relapsed/refractory (R/R)- AML requires improvement. In this study, we observed that combining homoharringtonine (HHT) with VEN plus azacitidine resulted in a significantly higher response and better survival than VA alone in patients with R/R-AML. Basic research indicates that HHT combined with VEN has a highly synergistic effect against both resistant AML cells and primary cells with/without mesenchymal stem cell (MSC) co-culture in vivo, inhibiting proliferation and colony-forming capacity of AML cells associated with concomitant cell cycle arrest. Mechanistically, HHT sensitizes AML cells to VEN by downregulating the anti-apoptotic proteins MCL-1/BCL-xL, activating reactive oxygen species (ROS), leading to mitochondrial membrane potential loss, and attenuating fatty acid (FA) uptake. These findings adding HHT to VEN-based regimens may enhance outcomes in R/R-AML patients.

Keywords:  Relapsed/refractory; acute myeloid leukemia; fatty acid uptake; homoharringtonine; reactive oxygen species; venetoclax

DOI:  https://doi.org/10.1080/10428194.2024.2400228
Cancer Biomark. 2024 Aug 02.

Glutaminase 1 plays critical roles in myelodysplastic syndrome and acute myeloid leukemia cells.

Seiichi Okabe, Mitsuru Moriyama, Yuya Arai, Akihiko Gotoh.

  BACKGROUND: Myelodysplastic syndrome (MDS) features bone marrow failure and a heightened risk of evolving into acute myeloid leukemia (AML), increasing with age and reducing overall survival. Given the unfavorable outcomes of MDS, alternative treatments are necessary. Glutamine, the most abundant amino acid in the blood, is metabolized first by the enzyme glutaminase (GLS).OBJECTIVES: To investigate whether GLS is involved in the progression of MDS. The efficacy of GLS inhibitors (CB839 or IPN60090) and BCL2 inhibitor venetoclax was also examined.
METHODS: We employed GLS inhibitors (CB839, IPN60090) and the BCL2 inhibitor venetoclax, prepared as detailed. MDS and AML cell lines were cultured under standard and modified (hypoxic, glutamine-free) conditions. Viability, proliferation, and caspase activity were assessed with commercial kits. RT-PCR quantified gene expression post-shRNA transfection. Mitochondrial potential, ATP levels, proteasome activity, and metabolic functions were evaluated using specific assays. Statistical analyses (t-tests, ANOVA) validated the findings.
RESULTS: The glutamine-free medium inhibited the growth of MDS cells. GLS1 expression was higher in AML cells than in normal control samples (GSE15061), whereas GLS2 expression was not. Treatment of MDS and AML cells for 72 h was inhibited in a dose-dependent manner by GLS inhibitors. Co-treatment with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax and GLS inhibitors increased potency. Cells transfected with GLS1 short hairpin RNA showed suppressed proliferation under hypoxic conditions and increased sensitivity to venetoclax.
CONCLUSIONS: Targeting glutaminolysis and BCL2 inhibition enhances the therapeutic efficacy and has been proposed as a novel strategy for treating high-risk MDS and AML.

Keywords:  AML; BCL-2 inhibitor; GLS inhibitor; Glutaminolysis; MDS; hypoxia

DOI:  https://doi.org/10.3233/CBM-230454
J Lipid Res. 2024 Aug 30. pii: S0022-2275(24)00143-3. [Epub ahead of print] 100638

Modification in mitochondrial function is associated with the FADS1 variant and its interaction with alpha-linolenic acid-enriched diet - an exploratory study.

Maija Vaittinen, Mariana Ilha, Ratika Sehgal, Maria A Lankinen, Jyrki Ågren, Pirjo Käkelä, Kirsi A Virtanen, Markku Laakso, Ursula Schwab, Jussi Pihlajamäki.

  Fatty acid desaturase (FADS1) variant-rs174550 strongly regulates polyunsaturated fatty acid (PUFA) biosynthesis. Additionally, the FADS1 has been shown to be related to mitochondrial function. Thus, we investigated whether changes in mitochondrial function are associated with the genetic variation in FADS1 (rs174550) in human adipocytes isolated from individuals consuming diets enriched with either dietary alpha-linolenic (ALA) or linoleic acid (LA). Two cohorts of men homozygous for the genotype of FADS1 (rs174550) were studied: FADSDIET2 dietary intervention study with ALA- and LA-enriched diets and Kuopio Obesity Surgery study (KOBS), respectively. We could demonstrate that differentiated human adipose-derived stromal cells from subjects with the TT genotype had higher mitochondrial metabolism compared with subjects with the CC genotype of FADS1-rs174550 in the FADSDIET2. Responses to PUFA-enriched diets differed between the genotypes of FADS1-rs174550, showing that ALA, but not LA, -enriched diet stimulated mitochondrial metabolism more in subjects with the CC genotype when compared with subjects with the TT genotype. ALA, but not LA, proportion in plasma phospholipid fraction correlated positively with adipose tissue mitochondrial-DNA amount in subjects with the CC genotype of FADS1-rs174550 in the KOBS. These findings demonstrate that the FADS1-rs174550 is associated with modification in mitochondrial function in human adipocytes. Additionally, subjects with the CC genotype, when compared with the TT genotype, benefit more from the ALA-enriched diet, leading to enhanced energy metabolism in human adipocytes. Altogether, the FADS1-rs174550 could be a genetic marker to identify subjects who are most suitable to receive dietary PUFA supplementation, establishing also a personalized therapeutic strategy to improve mitochondrial function in metabolic diseases.

Keywords:  Adipocytes; Alpha-linolenic acid; Dietary fat; FADS1; Fatty acid oxidation; Human adipose-derived stromal cell; Lipids/oxidation; Mitochondria; Omega-3 fatty acids; Polyunsaturated fatty acid

DOI:  https://doi.org/10.1016/j.jlr.2024.100638
Nutr Cancer. 2024 ;76(9): 789-814

Exploring the Relationship Between Diet, Lifestyle and Gut Microbiome in Colorectal Cancer Development: A Recent Update.

Biki Saha, Rithi A T, Subhamay Adhikary, Antara Banerjee, Arun Kumar Radhakrishnan, Asim K Duttaroy, Surajit Pathak.

Colorectal cancer (CRC) is one of the major causes of cancer-related mortality worldwide. Despite advances in treatment modalities, its prevalence continues to rise, notably among younger populations. Unhealthy dietary habits, sedentary routines, and obesity have been identified as one of the key contributors to the development of colorectal cancer, apart from genetic and epigenetic modifications. Recognizing the profound impact of diet and lifestyle on the intricate gut microbiota ecosystem offers a promising avenue for understanding CRC development and its treatment. Gut dysbiosis, characterized by imbalances favoring harmful microbes over beneficial ones, has emerged as a defining feature of CRC. Changes in diet and lifestyle can profoundly alter the composition of gut microbes and the metabolites they produce, potentially contributing to CRC onset. Focusing on recent evidence, this review discussed various dietary factors, such as high consumption of red and processed meats and low fiber intake, and lifestyle factors, including obesity, lack of physical activity, smoking, and excessive alcohol consumption, that influence the gut microbiome composition and elevate CRC risk.

DOI: https://doi.org/10.1080/01635581.2024.2367266
Prog Lipid Res. 2024 Aug 31. pii: S0163-7827(24)00033-X. [Epub ahead of print] 101300

Unraveling brain palmitic acid: Origin, levels and metabolic fate.

Mackenzie E Smith, Richard P Bazinet.

  In the human brain, palmitic acid (16:0; PAM) comprises nearly half of total brain saturates and has been identified as the third most abundant fatty acid overall. Brain PAM supports the structure of membrane phospholipids, provides energy, and regulates protein stability. Sources underlying the origin of brain PAM are both diet and endogenous synthesis via de novo lipogenesis (DNL), primarily from glucose. However, studies investigating the origin of brain PAM are limited to tracer studies utilizing labelled (14C/11C/3H/2H) PAM, and results vary based on the model and tracer used. Nevertheless, there is evidence PAM is synthesized locally in the brain, in addition to obtained directly from the diet. Herein, we provide an overview of brain PAM origin, entry to the brain, metabolic fate, and factors influencing brain PAM kinetics and levels, the latter in the context of age, as well as neurological diseases and psychiatric disorders. Additionally, we briefly summarize the role of PAM in signaling at the level of the brain. We add to the literature a rudimentary summary on brain PAM metabolism.

Keywords:  Brain; Levels; Metabolic fate; Neurological disease; Origin; Palmitic acid

DOI:  https://doi.org/10.1016/j.plipres.2024.101300
Cancer Biother Radiopharm. 2024 Aug 29.

WT1 And DNMT3A Mutations in Prognostic Significance of Acute Myeloid Leukemia: A Meta-Analysis.

Shiyue Ma, Lingjian Tang, Hui Tang, Chaoli Wu, Xue Pu, Jun Yang, Ninhong Niu.

  Background: Adult acute leukemia most commonly manifests as acute myeloid leukemia (AML), a highly heterogeneous malignant tumor of the blood system. The application of genetic diagnostic technology is currently prevalent in numerous clinical sectors. According to recent research, the presence of specific gene mutations or rearrangements in leukemia cells is the primary cause of the disease. As different types of leukemia are caused by atypical mutated genes, testing for these mutations or rearrangements can help diagnose leukemia and identify the disease's molecular targets for treatment. Methods: Using the search fields "WT1," "DNMT3A," "Acute myeloid leukemia," and "survival," the CBM, Cochrane Library, Scopus, EMBASE, and PUBMED databases were separately reviewed. The methodology for evaluating the risk of bias developed by the Cochrane Collaboration was used in conjunction with a methodical evaluation of pertinent literature. Excluded studies with the following characteristics: (1) incomplete and repetitive publications, (2) unable to retrieve or convert data, (3) non-English or Chinese articles. Results: This analysis included 13 studies covering a total of 3478 subjects. The frequency of Wilms' Tumor 1 (WT1) mutations is 6.7%-35.73%, and the frequency of DNMT3A mutations is 12.06%-51.1%. The remission rate of patients with WT1 mutations was less than that of patients without WT1 mutations (OR = 0.22; 95% confidence interval [CI]: 0.14, 0.36; p < 0.00001; I2 = 55%). The DNMT3A mutation has no statistical significance for the prognosis of AML (OR = 1.21; 95% CI: 0.93, 1.58; p = 0.16; I2 = 80%). After removing one study, the heterogeneity of the indicator (mitigation rate) among other studies of DNMT3A mutation was dramatically reduced (OR = 0.63; 95% CI: 0.43, 0.93; p = 0.02; I2 = 0%). Conclusions: Our meta-analysis shows that WT1 mutations hurt the remission rate of AML. Moreover, the impact of DNMT3A mutations on AML needs to be treated with caution. Gene diagnosis is critical for the prognosis and clinical management of AML.

Keywords:  DNMT3A; WT1; acute myeloid leukemia; genetic testing; meta-analysis

DOI:  https://doi.org/10.1089/cbr.2024.0093
Sci Rep. 2024 09 04. 14(1): 20575

The compartment-specific manipulation of the NAD+/NADH ratio affects the metabolome and the function of glioblastoma.

Myunghoon Lee, Jae Hong Yoo, Inseo Kim, Sinbeom Kang, Wonsik Lee, Sungjin Kim, Kyung-Seok Han.

  Glioblastoma multiforme (GBM) is the most aggressive type of cancer in the brain and has an inferior prognosis because of the lack of suitable medicine, largely due to its tremendous invasion. GBM has selfish metabolic pathways to promote migration, invasion, and proliferation compared to normal cells. Among various metabolic pathways, NAD (nicotinamide adenine dinucleotide) is essential in generating ATP and is used as a resource for cancer cells. LbNOX (Lactobacillus brevis NADH oxidase) is an enzyme that can directly manipulate the NAD+/NADH ratio. In this study, we found that an increased NAD+/NADH ratio by LbNOX or mitoLbNOX reduced intracellular glutamate and calcium responses and reduced invasion capacity in GBM. However, the invasion was not affected in GBM by rotenone, an ETC (Electron Transport Chain) complex I inhibitor, or nicotinamide riboside, a NAD+ precursor, suggesting that the crucial factor is the NAD+/NADH ratio rather than the absolute quantity of ATP or NAD+ for the invasion of GBM. To develop a more accurate and effective GBM treatment, our findings highlight the importance of developing a new medicine that targets the regulation of the NAD+/NADH ratio, given the current lack of effective treatment options for this brain cancer.

Keywords:   LbNOX; Glioblastoma; Glutamate; Invasion; NAD+/NADH

DOI:  https://doi.org/10.1038/s41598-024-71462-8
Clin Lymphoma Myeloma Leuk. 2024 Aug 03. pii: S2152-2650(24)00261-1. [Epub ahead of print]

Safety, Efficacy, and Predictive Factors of Venetoclax-Based Regimens in Elderly Acute Myeloid Leukemia Patients: A Meta-Analysis.

Zaheer Qureshi, Faryal Altaf, Abdur Jamil, Rimsha Siddique.

  Venetoclax synergizes with low-intensity regimens such as hypomethylating agents (HMAs) and low-dose cytarabine (LDAC). However, less is known about the clinical activity of venetoclax combined with HMAs or LDAC. Therefore, the current study focused on assessing the clinical efficacy, safety, and predictive factors for response to these venetoclax-based regimens in elderly patients with acute myeloid leukemia (AML). A comprehensive search for literature related to our study objective was performed on PubMed, Embase, Web of Science, and Google Scholar databases. The statistical analyses were performed using Review Manager or the Comprehensive Meta-Analysis software. In addition, methodological quality evaluation of nonrandomized studies was conducted using the Newcastle Ottawa Scale, while bias assessment of randomized studies was performed with Cochrane's risk of bias tool. Twelve studies, including 1432 elderly AML patients treated with venetoclax-based regimens, were identified for review and analysis. The pooled analysis showed that the rate of complete response with or without incomplete blood count recovery (CR/CRi) and overall response rate (ORR) among patients treated with venetoclax and HMAs was 59% and 64%, respectively. On the other hand, an CR/CRi of 50% was observed in patients treated with venetoclax and LDAC. Furthermore, venetoclax combined with HMAs demonstrated a significant survival benefit over HMAs alone and intensive chemotherapy (HR: 0.57; 95% CI: 0.47-0.68; P < .00001). The most common grade ≥ 3 hematologic disorder, nonhematological event, and infection in AML patients treated with venetoclax and HMAs were febrile neutropenia (39%), hypokalemia (12%), and pneumonia (19%), respectively. Conversely, thrombocytopenia, hypokalemia, and pneumonia were more common in patients treated with venetoclax and LDAC (41%, 15%, and 12%, respectively). Venetoclax combined with HMAs or LDAC has good clinical activity and a manageable safety profile in elderly patients with AML.

Keywords:  Cytarabine; Hypomethylating agents; Venetocalx

DOI:  https://doi.org/10.1016/j.clml.2024.07.004
Dis Model Mech. 2024 Aug 01. pii: dmm050775. [Epub ahead of print]17(8):

Understanding the interplay between dNTP metabolism and genome stability in cancer.

Miriam Yagüe-Capilla, Sean G Rudd.

  The size and composition of the intracellular DNA precursor pool is integral to the maintenance of genome stability, and this relationship is fundamental to our understanding of cancer. Key aspects of carcinogenesis, including elevated mutation rates and induction of certain types of DNA damage in cancer cells, can be linked to disturbances in deoxynucleoside triphosphate (dNTP) pools. Furthermore, our approaches to treat cancer heavily exploit the metabolic interplay between the DNA and the dNTP pool, with a long-standing example being the use of antimetabolite-based cancer therapies, and this strategy continues to show promise with the development of new targeted therapies. In this Review, we compile the current knowledge on both the causes and consequences of dNTP pool perturbations in cancer cells, together with their impact on genome stability. We outline several outstanding questions remaining in the field, such as the role of dNTP catabolism in genome stability and the consequences of dNTP pool expansion. Importantly, we detail how our mechanistic understanding of these processes can be utilised with the aim of providing better informed treatment options to patients with cancer.

Keywords:  Cancer; DNA repair; Deoxynucleoside triphosphate (dNTP) metabolism; Genome stability

DOI:  https://doi.org/10.1242/dmm.050775
Mitochondrion. 2024 Sep 03. pii: S1567-7249(24)00110-7. [Epub ahead of print]79 101952

SDHAF2 facilitates mitochondrial respiration through stabilizing succinate dehydrogenase and cytochrome c oxidase assemblies.

Chang-Lin Chen, Takaya Ishihara, Soumyadip Pal, Wei-Ling Huang, Emi Ogasawara, Chuang-Rung Chang, Naotada Ishihara.

  Succinate dehydrogenase (SDH) plays pivotal roles in maintaining cellular metabolism, modulating regulatory control over both the tricarboxylic acid cycle and oxidative phosphorylation to facilitate energy production within mitochondria. Given that SDH malfunction may serve as a hallmark triggering pseudo-hypoxia signaling and promoting tumorigenesis, elucidating the impact of SDH assembly defects on mitochondrial functions and cellular responses is of paramount importance. In this study, we aim to clarify the role of SDHAF2, one assembly factor of SDH, in mitochondrial respiratory activities. To achieve this, we utilize the CRISPR/Cas9 system to generate SDHAF2 knockout in HeLa cells and examine mitochondrial respiratory functions. Our findings demonstrate a substantial reduction in oxygen consumption rate in SDHAF2 knockout cells, akin to cells with inhibited SDH activity. In addition, in our in-gel activity assays reveal a significant decrease not only in SDH activity but also in cytochrome c oxidase (COX) activity in SDHAF2 knockout cells. The reduced COX activity is attributed to the assembly defect and remains independent of SDH inactivation or SDH complex disassembly. Together, our results indicate a critical role of SDHAF2 in regulating respiration by facilitating the assembly of COX.

Keywords:  Cytochrome c oxidase; Oxidative phosphorylation; Succinate dehydrogenase assembly factor 2 (SDHAF2)

DOI:  https://doi.org/10.1016/j.mito.2024.101952
Nutr Rev. 2024 Aug 30. pii: nuae105. [Epub ahead of print]

The Clinical Impact of Time-restricted Eating on Cancer: A Systematic Review.

Eleah J Stringer, Rob W G Cloke, Lindsay Van der Meer, Rachel A Murphy, Nicol A Macpherson, Julian J Lum.

  CONTEXT: In the face of the growing global burden of cancer, there is increasing interest in dietary interventions to mitigate its impacts. Pre-clinical evidence suggests that time-restricted eating (TRE), a type of intermittent fasting, induces metabolic effects and alterations in the gut microbiome that may impede carcinogenesis. Research on TRE in cancer has progressed to human studies, but the evidence has yet to be synthesized.OBJECTIVE: The objective of this study was to systematically evaluate the clinical and/or metabolomic effects of TRE compared with ad libitum eating or alternative diets in people with cancer.
DATA SOURCES: Ovid MEDLINE, Ovid Embase, CINAHL, Ovid Cochrane Central Register of Control Trials (CENTRAL), Web of Science Core Collection (ESCI, CPCI-SSH, CPCI-S), and SCOPUS were searched up to January 4, 2023, using the core concepts of "intermittent fasting" and "cancer." Original study designs, protocols, and clinical trial registries were included.
DATA EXTRACTION: After evaluating 13 900 results, 24 entries were included, consisting of 8 full articles, 2 abstracts, 1 published protocol and 13 trial registries. All data were extracted, compared, and critically analyzed.
DATA ANALYSIS: There was heterogeneity in the patient population (eg, in tumor sites), TRE regimens (eg, degree of restriction, duration), and clinical end points. A high rate (67-98%) of TRE adherence was observed, alongside improvements in quality of life. Four articles assessed cancer markers and found a reduction in tumor marker carcinoembryonic antigen, reduced rates of recurrence, and a sustained major molecular response, following TRE. Five articles demonstrated modified cancer risk factors, including beneficial effects on body mass index, adiposity, glucoregulation, and inflammation in as short a period as 8 weeks. None of the completed studies assessed the effect of TRE on the microbiome, but analysis of the microbiome is a planned outcome in 2 clinical trials.
CONCLUSIONS: Preliminary findings suggest that TRE is feasible and acceptable by people with cancer, may have oncological benefits, and improves quality of life.
REGISTRATION: PROSPERO registration No. CRD42023386885.

Keywords:  cancer; dietary interventions; intermittent fasting; systematic review; time-restricted eating

DOI:  https://doi.org/10.1093/nutrit/nuae105
Blood Rev. 2024 Aug 29. pii: S0268-960X(24)00071-7. [Epub ahead of print] 101238

Ven the dose matters: Venetoclax dosing in the frontline treatment of AML.

Dahniel Sastow, Hannah Levavi, Nicole Wagner, Keith Pratz, Douglas Tremblay.

  Older/unfit adults with AML have worse outcomes and fewer treatment options than their younger/fit counterparts. In vitro studies have found a synergistic effect of hypomethylating agents (HMA) with venetoclax (VEN) on AML cells and since the phase 3 VIALE-A trial demonstrated a survival benefit, HMA + VEN has become the standard of care in the frontline setting for older/unfit adults with AML. Unfortunately, the standard 28-day cycle of VEN is associated with a high degree of myelosuppression leading to treatment delays and dose modifications. Many small retrospective studies have successfully shown comparable outcomes to VIALE-A with reduced dose/duration of VEN. Furthermore, low dose metronomic dosing of HMA + VEN has shown clinical benefit while minimizing myelotoxicity. Future trials are vital to understand the appropriate dose of VEN in combination with HMA, to evaluate HMA + VEN compared to intensive therapy for younger/fit patients, and to explore its utility in the relapsed/refractory setting.

Keywords:  AML; Dosing; Reduction; Toxicity; Venetoclax

DOI:  https://doi.org/10.1016/j.blre.2024.101238
Eur J Nutr. 2024 Sep 04.

Are there interindividual differences in the reactive hypoglycaemia response to breakfast? A replicate crossover trial.

Javier T Gonzalez, Lorenzo Lolli, Rachel C Veasey, Penny L S Rumbold, James A Betts, Greg Atkinson, Emma J Stevenson.

  BACKGROUND: Following consumption of a meal, circulating glucose concentrations can rise and then fall briefly below the basal/fasting concentrations. This phenomenon is known as reactive hypoglycaemia but to date no researcher has explored potential inter-individual differences in response to meal consumption.OBJECTIVE: We conducted a secondary analysis of existing data to examine inter-individual variability of reactive hypoglycaemia in response to breakfast consumption.
METHODS: Using a replicate crossover design, 12 healthy, physically active men (age: 18-30 y, body mass index: 22.1 to 28.0 kg⋅m- 2) completed two identical control (continued overnight fasting) and two breakfast (444 kcal; 60% carbohydrate, 17% protein, 23% fat) conditions in randomised sequences. Blood glucose and lactate concentrations, serum insulin and non-esterified fatty acid concentrations, whole-body energy expenditure, carbohydrate and fat oxidation rates, and appetite ratings were determined before and 2 h after the interventions. Inter-individual differences were explored using Pearson's product-moment correlations between the first and second replicates of the fasting-adjusted breakfast response. Within-participant covariate-adjusted linear mixed models and a random-effects meta-analytical approach were used to quantify participant-by-condition interactions.
RESULTS: Breakfast consumption lowered 2-h blood glucose by 0.44 mmol/L (95%CI: 0.76 to 0.12 mmol/L) and serum NEFA concentrations, whilst increasing blood lactate and serum insulin concentrations (all p < 0.01). Large, positive correlations were observed between the first and second replicates of the fasting-adjusted insulin, lactate, hunger, and satisfaction responses to breakfast consumption (all r > 0.5, 90%CI ranged from 0.03 to 0.91). The participant-by-condition interaction response variability (SD) for serum insulin concentration was 11 pmol/L (95%CI: 5 to 16 pmol/L), which was consistent with the τ-statistic from the random-effects meta-analysis (11.7 pmol/L, 95%CI 7.0 to 22.2 pmol/L) whereas effects were unclear for other outcome variables (e.g., τ-statistic value for glucose: 0 mmol/L, 95%CI 0.0 to 0.5 mmol/L).
CONCLUSIONS: Despite observing reactive hypoglycaemia at the group level, we were unable to detect any meaningful inter-individual variability of the reactive hypoglycaemia response to breakfast. There was, however, evidence that 2-h insulin responses to breakfast display meaningful inter-individual variability, which may be explained by relative carbohydrate dose ingested and variation in insulin sensitivity of participants.

Keywords:  Breakfast; Carbohydrate; Glucose; Metabolism; Response heterogeneity

DOI:  https://doi.org/10.1007/s00394-024-03467-y
Proteomics Clin Appl. 2024 Sep 03. e202400008

Analysis of Unfolded Protein Response Activation in Colon Adenocarcinoma Epithelial Cells: A Proteomic Study.

Solange Vivier, Fabrice Bray, Stéphanie Flament, Lucile Guilbert, Florence Renaud, Christian Rolando, David Launay, Sylvain Dubucquoi, Vincent Sobanski.

  PURPOSE: High throughput technologies have identified molecular patterns in colorectal cancer (CRC) cells, aiding in modeling responses to anti-cancer treatments. The different responses observed depend on the type of cancer, the tumour grade and the functional programme of the cancer cells. Recent studies suggest that the unfolded protein response (UPR), autophagy and apoptosis could be involved in treatment resistance mechanisms by interacting with the tumour microenvironment (TME).EXPERIMENTAL DESIGN: We analysed by LC-MS/MS the proteome of two representative colon adenocarcinoma epithelial cell lines from different tumour grades (CCL-233 and CCL-221) at the basal state or after the UPR induction.
RESULTS: Cell lines expressed a different proteome on about 10% of their total proteins identified, especially on UPR, autophagy and apoptosis pathways proteins at basal state. After UPR induction, the proteome of the cells was modified with a greater adaptive response to cellular stress in CCL-221 cells where the UPR was strongly activated at the basal state.
CONCLUSIONS AND CLINICAL RELEVANCE: CRC cell lines at different tumour grades expressed different functional programmes at the proteomic level and were characterised by different responses to the UPR induction. This study suggests that baseline cancer cell stress status could have an impact on the efficiency of cancer therapies.

Keywords:  LC‐MS/MS; colorectal cancer; endoplasmic reticulum stress; epithelial cells; unfolded protein response

DOI:  https://doi.org/10.1002/prca.202400008
Asian Pac J Cancer Prev. 2024 Aug 01. pii: 91295. [Epub ahead of print]25(8): 2951-2962

Impact of Serum Ferritin and Iron Overload on Acute Myeloid Leukemia Outcomes: A Systematic Review and Meta-Analysis.

Sanambar Sadighi, Efe Sahinoglu, Ahmed Haider Kubba, Jhanvi Patel, Forough Hosseini, Mohammad Ali Shafiee, Bakhtavar Qureshi.

  OBJECTIVE: To evaluate the iron overload among individuals with acute myeloid leukemia (AML) who have not received red blood cell transfusions.METHODS: A comprehensive search was conducted in Embase, PubMed, PubMed Central, Web of Science, NIH, and Blood Library databases up to September 2023. The search strategy included keywords related to AML, iron overload, serum ferritin, survival, outcomes, and inflammation. Manual searches through included articles and relevant references were also performed. From 1650 initial articles, 16 studies involving 8752 patients met the inclusion criteria for systematic review. Statistical analysis used hazard ratios (HR) and confidence intervals (CI). Results: The systematic review and meta-analysis revealed a statistically significant association between high serum ferritin (SF) levels and poor outcomes in AML patients before starting chemotherapy. Elevated SF levels (>1000 mg/L) were associated with lower overall survival (OS) and event-free survival (EFS) (HR for OS: 1.99, 95% CI: 1.48-2.66; HR for EFS: 2.29, 95% CI: 1.73-3.05). Elevated SF levels were inversely correlated with the gradual onset of infections, indicating an increased risk of early mortality (p<0.05).
CONCLUSION: Elevated serum ferritin levels are significantly associated with poor outcomes in AML patients before treatment initiation. These findings highlight the importance of monitoring iron levels in these patients to improve prognostic assessments and treatment strategies.

Keywords:  Serum ferritin; acute myeloid leukemia; iron overload; survival

DOI:  https://doi.org/10.31557/APJCP.2024.25.8.2951
Acta Pharm Sin B. 2024 Aug;14(8): 3493-3512

Phenylalanine deprivation inhibits multiple myeloma progression by perturbing endoplasmic reticulum homeostasis.

Longhao Cheng, Xiaoxue Wang, Aijun Liu, Ying Zhu, Hu Cheng, Jiangling Yu, Lili Gong, Honglin Liu, Guolin Shen, Lihong Liu.

  Amino acid metabolic remodeling is a hallmark of cancer, driving an increased nutritional demand for amino acids. Amino acids are pivotal for energetic regulation, biosynthetic support, and homeostatic maintenance to stimulate cancer progression. However, the role of phenylalanine in multiple myeloma (MM) remains unknown. Here, we demonstrate that phenylalanine levels in MM patients are decreased in plasma but elevated in bone marrow (BM) cells. After the treatment, phenylalanine levels increase in plasma and decrease in BM. This suggests that changes in phenylalanine have diagnostic value and that phenylalanine in the BM microenvironment is an essential source of nutrients for MM progression. The requirement for phenylalanine by MM cells exhibits a similar pattern. Inhibiting phenylalanine utilization suppresses MM cell growth and provides a synergistic effect with Bortezomib (BTZ) treatment in vitro and murine models. Mechanistically, phenylalanine deprivation induces excessive endoplasmic reticulum stress and leads to MM cell apoptosis through the ATF3-CHOP-DR5 pathway. Interference with ATF3 significantly affects phenylalanine deprivation therapy. In conclusion, we have identified phenylalanine metabolism as a characteristic feature of MM metabolic remodeling. Phenylalanine is necessary for MM proliferation, and its aberrant demand highlights the importance of low-phenylalanine diets as an adjuvant treatment for MM.

Keywords:  ATF3; Amino acid metabolism; Apoptosis; Cancer therapy; Endoplasmic reticulum stress; Multiple myeloma; Nutrient deprivation; Phenylalanine

DOI:  https://doi.org/10.1016/j.apsb.2024.04.021
J Mol Med (Berl). 2024 Aug 29.

TRAP1 modulates mitochondrial biogenesis via PGC-1α/TFAM signalling pathway in colorectal cancer cells.

Giuseppina Bruno, Michele Pietrafesa, Fabiana Crispo, Annamaria Piscazzi, Francesca Maddalena, Guido Giordano, Vincenza Conteduca, Marianna Garofoli, Almudena Porras, Franca Esposito, Matteo Landriscina.

  Metabolic rewiring promotes cancer cell adaptation to a hostile microenvironment, representing a hallmark of cancer. This process involves mitochondrial function and is mechanistically linked to the balance between mitochondrial biogenesis (MB) and mitophagy. The molecular chaperone TRAP1 is overexpressed in 60-70% of human colorectal cancers (CRC) and its over-expression correlates with poor clinical outcome, being associated with many cancer cell functions (i.e. adaptation to stress, protection from apoptosis and drug resistance, protein synthesis quality control, metabolic rewiring from glycolysis to mitochondrial respiration and vice versa). Here, the potential new role of TRAP1 in regulating mitochondrial dynamics was investigated in CRC cell lines and human CRCs. Our results revealed an inverse correlation between TRAP1 and mitochondrial-encoded respiratory chain proteins both at transcriptional and translational levels. Furthermore, TRAP1 silencing is associated with increased mitochondrial mass and mitochondrial DNA copy number (mtDNA-CN) as well as enhanced MB through PGC-1α/TFAM signalling pathway, promoting the formation of new functioning mitochondria and, likely, underlying the metabolic shift towards oxidative phosphorylation. These results suggest an involvement of TRAP1 in regulating MB process in human CRC cells. KEY MESSAGES: TRAP1 inversely correlates with protein-coding mitochondrial gene expression in CRC cells and tumours. TRAP1 silencing correlates with increased mitochondrial mass and mtDNA copy number in CRC cells. TRAP1 silencing favours mitochondrial biogenesis in CRC cells.

Keywords:  Colorectal cancer; Metabolism; Mitochondrial biogenesis; Peroxisome proliferation-activated receptor gamma coactivator α1-alpha; TNF receptor-associated protein 1; Transcription factor A mitochondrial

DOI:  https://doi.org/10.1007/s00109-024-02479-9