bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2024–02–11
23 papers selected by
Brett Chrest, East Carolina University
  1. Metabolic Signature of Warburg Effect in Cancer: An Effective and Obligatory Interplay between Nutrient Transporters and Catabolic/Anabolic Pathways to Promote Tumor Growth.
  2. Altered Oxidative Phosphorylation Confers Vulnerability on IDH1-Mutant Leukemia Cells: Is This Therapeutically Tractable?
  3. A metabolic-epigenetic mechanism directs cell fate and therapeutic sensitivity in breast cancer.
  4. Metabolomic Investigations into Hypoxia-Mediated Metabolic Reprogramming of Pancreatic Cancer Cells.
  5. Detection of NADH and NADPH levels in vivo identifies shift of glucose metabolism in cancer to energy production.
  6. Ketogenic diet for epilepsy and obesity: Is it the same?
  7. Feasible diet and circadian interventions reduce in vivo progression of FLT3-ITD-positive acute myeloid leukemia.
  8. Lipid droplets provide metabolic flexibility for cancer progression.
  9. Sex-Specific Effects of Ketogenic Diet on Anxiety-like Behavior and Neuroimmune Response in C57Bl/6J Mice.
  10. Isoproterenol Alters Metabolism, Promotes Survival and Migration in 5-Fluorouracil-Treated SW480 Cells with and without Beta-hydroxybutyrate.
  11. Circulating metabolome landscape in Lynch syndrome.
  12. Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding.
  13. Targeting MYC induces lipid droplet accumulation by upregulation of HILPDA in clear cell renal cell carcinoma.
  14. Brain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport.
  15. Sex-specific molecular differences in glioblastoma: assessing the clinical significance of genetic variants.
  16. Patient-Derived Models of Cancer in the NCI PDMC Consortium: Selection, Pitfalls, and Practical Recommendations.
  17. Palmitoylation alters LDHA activity and pancreatic cancer response to chemotherapy.
  18. Effect of exogenous and endogenous ketones on respiratory exchange ratio and glucose metabolism in healthy subjects.
  19. Interorgan rhythmicity as a feature of healthful metabolism.
  20. How the 'Aerobic/Anaerobic Glycolysis' Meme Formed a 'Habit of Mind' Which Impedes Progress in the Field of Brain Energy Metabolism.
  21. Live Organoid Cyclic Imaging.
  22. Biomarkers of Response to Venetoclax Therapy in Acute Myeloid Leukemia.
  23. Retinoblastoma vulnerability to combined de novo and salvage pyrimidine ribonucleotide synthesis pharmacologic blockage.
  1. Cancers (Basel). 2024 Jan 24. pii: 504. [Epub ahead of print]16(3):
    Metabolic Signature of Warburg Effect in Cancer: An Effective and Obligatory Interplay between Nutrient Transporters and Catabolic/Anabolic Pathways to Promote Tumor Growth.
    Marilyn Mathew, Nhi T Nguyen, Yangzom D Bhutia, Sathish Sivaprakasam, Vadivel Ganapathy.
      Aerobic glycolysis in cancer cells, originally observed by Warburg 100 years ago, which involves the production of lactate as the end product of glucose breakdown even in the presence of adequate oxygen, is the foundation for the current interest in the cancer-cell-specific reprograming of metabolic pathways. The renewed interest in cancer cell metabolism has now gone well beyond the original Warburg effect related to glycolysis to other metabolic pathways that include amino acid metabolism, one-carbon metabolism, the pentose phosphate pathway, nucleotide synthesis, antioxidant machinery, etc. Since glucose and amino acids constitute the primary nutrients that fuel the altered metabolic pathways in cancer cells, the transporters that mediate the transfer of these nutrients and their metabolites not only across the plasma membrane but also across the mitochondrial and lysosomal membranes have become an integral component of the expansion of the Warburg effect. In this review, we focus on the interplay between these transporters and metabolic pathways that facilitates metabolic reprogramming, which has become a hallmark of cancer cells. The beneficial outcome of this recent understanding of the unique metabolic signature surrounding the Warburg effect is the identification of novel drug targets for the development of a new generation of therapeutics to treat cancer.
    Keywords:  aerobic glycolysis; glutamine addiction; glutaminolysis; lactate receptors; nutrient transporters; oncogenes; oncometabolites; one-carbon metabolism; reductive carboxylation; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers16030504
  2. Blood Cancer Discov. 2024 Feb 08. OF1-OF3
    Altered Oxidative Phosphorylation Confers Vulnerability on IDH1-Mutant Leukemia Cells: Is This Therapeutically Tractable?
    David P Steensma.
       SUMMARY: Isocitrate dehydrogenase (IDH)-mutant acute myeloid leukemia (AML) is treatable with inhibitors of mutant IDH and also responds well to combination therapies including venetoclax, but most patients with IDH-mutant AML either never achieve complete remission or relapse because mutant hematopoietic stem cells persist despite treatment. An interesting new study in Blood Cancer Discovery characterizes a specific vulnerability in the mitochondrial oxidative phosphorylation system in preleukemic hematopoietic stem cells from patients with IDH1 mutations that is not present in those with IDH2 mutations; will this susceptibility prove amenable to therapy? See related article by Landberg et al. (10).
    DOI:  https://doi.org/10.1158/2643-3230.BCD-23-0255
  3. Cancer Res. 2024 Feb 08.
    A metabolic-epigenetic mechanism directs cell fate and therapeutic sensitivity in breast cancer.
    Matthew J Bernard, Andrew S Goldstein.
      Over the past decade, studies have increasingly shed light on a reciprocal relationship between cellular metabolism and cell fate, meaning that a cell's lineage both drives and is governed by its specific metabolic features. A recent study by Zhang and colleagues, published in Cell Metabolism, describes a novel metabolic-epigenetic regulatory axis that governs lineage identity in triple negative breast cancer (TNBC). Among the key findings, the authors demonstrate that the metabolic enzyme pyruvate kinase M2 (PKM2) directly binds to the histone methyltransferase enhancer of zeste homologue 2 (EZH2) in the nucleus to silence expression of a set of genes that includes the mitochondrial carnitine transporter SLC16A9. Perturbation of this metabolic-epigenetic regulatory mechanism induces a metabolic shift away from glycolysis and towards fatty acid oxidation. The ensuing influx of carnitine facilitates the deposition of the activating epigenetic mark H3K27Ac onto the promoter of GATA3, driving a committed luminal lineage state. Importantly, this metabolic-epigenetic axis represents a potentially targetable vulnerability for the treatment of TNBC, a subtype that currently lacks effective therapeutic strategies. These findings lend further support for the paradigm shift underlying our understanding of cancer metabolism: that a cellular fuel source functions not only to provide energy but also to direct the epigenetic regulation of cell fate.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0460
  4. Methods Mol Biol. 2024 ;2755 191-200
    Metabolomic Investigations into Hypoxia-Mediated Metabolic Reprogramming of Pancreatic Cancer Cells.
    Vira Chumak, Girish H Rajacharya, Pankaj K Singh.
      Hypoxia is a crucial microenvironmental factor that defines tumor cell growth and aggressiveness. Cancer cells adapt to hypoxia by altering their metabolism. These alterations impact various cellular and physiological functions, including energy metabolism, vascularization, invasion and metastasis, genetic instability, cell immortalization, stem cell maintenance, and resistance to chemotherapy (Li et al. Technol Cancer Res Treat 20:15330338211036304, 2021). Hypoxia-inducible factor-1α (HIF-1α) is known to be a critical regulator of glycolysis that directly regulates the transcription of multiple key enzymes of the glycolysis pathway. Moreover, HIF-1α stabilization can be directly modulated by TCA-derived metabolites, including 2-ketoglutarate and succinate (Infantino et al, Int J Mol Sci 22(22), https://doi.org/10.3390/ijms22115703 , 2021). Overall, the molecular mechanisms underlying the adaptation of cellular metabolism to hypoxia impact the metabolic phenotype of cancer cells. Such adaptations include increased glucose uptake, increased lactate production, and increased levels of other metabolites that stabilize HIF-1α, leading to a vicious circle of hypoxia-induced tumor growth.
    Keywords:  HIF; Hypoxia; Metabolomics; Pancreatic cancer; Tandem mass spectrometry
    DOI:  https://doi.org/10.1007/978-1-0716-3633-6_14
  5. FEBS J. 2024 Feb 05.
    Detection of NADH and NADPH levels in vivo identifies shift of glucose metabolism in cancer to energy production.
    Elena V Potapova, Evgenii A Zherebtsov, Valery V Shupletsov, Viktor V Dremin, Ksenia Y Kandurova, Andrian V Mamoshin, Andrey Y Abramov, Andrey V Dunaev.
      Profound changes in the metabolism of cancer cells have been known for almost 100 years, and many aspects of these changes have continued to be actively studied and discussed. Differences in the results of various studies can be explained by the diversity of tumours, which have differing processes of energy metabolism, and by limitations in the methods used. Here, using fluorescence lifetime needle optical biopsy in a hepatocellular carcinoma (HCC) mouse model and patients with HCC, we measured reduced nicotinamide adenine dinucleotide (NADH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) in control liver, and in HCC tumours and their adjacent regions. We found that NADH level (mostly responsible for energy metabolism) is increased in tumours but also in adjacent regions of the same liver. NADPH level is significantly decreased in the tumours of patients but increased in the HCC mouse model. However, in the ex vivo tumour slices of mouse HCC, reactive oxygen species production and glutathione level (both dependent on NADPH) were significantly suppressed. Thus, glucose-dependent NADH and NADPH production in tumours changed but with a more pronounced shift to energy production (NADH), rather than NADPH synthesis for redox balance.
    Keywords:  energy metabolism; fluorescence lifetime; hepatocellular carcinoma; liver cancer; optical biopsy
    DOI:  https://doi.org/10.1111/febs.17067
  6. Nutr Metab Cardiovasc Dis. 2024 Jan 14. pii: S0939-4753(24)00016-4. [Epub ahead of print]
    Ketogenic diet for epilepsy and obesity: Is it the same?
    A Tagliabue, M Armeno, K A Berk, M Guglielmetti, C Ferraris, J Olieman, E van der Louw.
      The term "ketogenic diet" (KD) is used for a wide variety of diets with diverse indications ranging from obesity to neurological diseases, as if it was the same diet. This terminology is confusing for patients and the medical and scientific community. The term "ketogenic" diet implies a dietary regimen characterized by increased levels of circulating ketone bodies that should be measured in blood (beta-hydroxybutyrate), urine (acetoacetate) or breath (acetone) to verify the "ketogenic metabolic condition". Our viewpoint highlights that KDs used for epilepsy and obesity are not the same; the protocols aimed at weight loss characterized by low-fat, low-CHO and moderate/high protein content are not ketogenic by themselves but may become mildly ketogenic when high calorie restriction is applied. In contrast, there are standardized protocols for neurological diseases treatment for which ketosis has been established to be part of the mechanism of action. Therefore, in our opinion, the term ketogenic dietary therapy (KDT) should be reserved to the protocols considered for epilepsy and other neurological diseases, as suggested by the International Study Group in 2018. We propose to adjust the abbreviations in VLCHKD for Very Low CarboHydrate Ketogenic Diet and VLEKD for Very Low Energy Ketogenic Diet, to clarify the differences in dietary composition. We recommend that investigators describe the researchers describing efficacy or side effects of KDs, to clearly specify the dietary protocol used with its unique acronym and level of ketosis, when ketosis is considered as a component of the diet's mechanism of action.
    Keywords:  Epilepsy; Ketogenic diet; Obesity; Very low calorie ketogenic diet; Very low carbohydrates ketogenic diet
    DOI:  https://doi.org/10.1016/j.numecd.2024.01.014
  7. Cancer Med. 2024 Jan;13(2): e6949
    Feasible diet and circadian interventions reduce in vivo progression of FLT3-ITD-positive acute myeloid leukemia.
    Megan Rodriguez, Baharan Fekry, Brianna Murphy, Mary Figueroa, Tiewei Cheng, Margaret Raber, Lisa Wartenberg, Donna Bell, Lisa Triche, Karla Crawford, Huaxian Ma, Kendra Allton, Ruwaida Ahmed, Jaime Tran, Christine Ranieri, Marina Konopleva, Michelle Barton, Cesar Nunez, Kristin Eckel-Mahan, Joya Chandra.
       BACKGROUND: Acute myeloid leukemia (AML) with an internal tandem duplication in the fms-like tyrosine kinase receptor 3 gene (FLT3-ITD) is associated with poor survival, and few studies have examined the impact of modifiable behaviors, such as nutrient quality and timing, in this subset of acute leukemia.
    METHODS: The influence of diet composition (low-sucrose and/or low-fat diets) and timing of diet were tested in tandem with anthracycline treatment in orthotopic xenograft mouse models. A pilot clinical study to test receptivity of pediatric leukemia patients to macronutrient matched foods was conducted. A role for the circadian protein, BMAL1 (brain and muscle ARNT-like 1), in effects of diet timing was studied by overexpression in FLT3-ITD-bearing AML cells.
    RESULTS: Reduced tumor burden in FLT3-ITD AML-bearing mice was observed with interventions utilizing low-sucrose and/or low-fat diets, or time-restricted feeding (TRF) compared to mice fed normal chow ad libitum. In a tasting study, macronutrient matched low-sucrose and low-fat meals were offered to pediatric acute leukemia patients who largely reported liking the meals. Expression of the circadian protein, BMAL1, was heightened with TRF and the low-sucrose diet. BMAL1 overexpression and treatment with a pharmacological inducer of BMAL1 was cytotoxic to FLT3-ITD AML cells.
    CONCLUSIONS: Mouse models for FLT3-ITD AML show that diet composition and timing slows progression of FLT3-ITD AML growth in vivo, potentially mediated by BMAL1. These interventions to enhance therapy efficacy show preliminary feasibility, as pediatric leukemia patients responded favorable to preparation of macronutrient matched meals.
    Keywords:  acute myeloid leukemia; circadian rhythm; diet; time-restricted feeding
    DOI:  https://doi.org/10.1002/cam4.6949
  8. FEBS Lett. 2024 Feb 07.
    Lipid droplets provide metabolic flexibility for cancer progression.
    Rémi Safi, Pablo Menéndez, Albert Pol.
      A hallmark of cancer cells is their remarkable ability to efficiently adapt to favorable and hostile environments. Due to a unique metabolic flexibility, tumor cells can grow even in the absence of extracellular nutrients or in stressful scenarios. To achieve this, cancer cells need large amounts of lipids to build membranes, synthesize lipid-derived molecules, and generate metabolic energy in the absence of other nutrients. Tumor cells potentiate strategies to obtain lipids from other cells, metabolic pathways to synthesize new lipids, and mechanisms for efficient storage, mobilization, and utilization of these lipids. Lipid droplets (LDs) are the organelles that collect and supply lipids in eukaryotes and it is increasingly recognized that the accumulation of LDs is a new hallmark of cancer cells. Furthermore, an active role of LD proteins in processes underlying tumorigenesis has been proposed. Here, by focusing on three major classes of LD-resident proteins (perilipins, lipases, and acyl-CoA synthetases), we provide an overview of the contribution of LDs to cancer progression and discuss the role of LD proteins during the proliferation, invasion, metastasis, apoptosis, and stemness of cancer cells.
    Keywords:  cancer; invasion; lipid droplets; lipids; metastasis; tumorigenesis
    DOI:  https://doi.org/10.1002/1873-3468.14820
  9. J Nutr Biochem. 2024 Feb 02. pii: S0955-2863(24)00024-X. [Epub ahead of print] 109591
    Sex-Specific Effects of Ketogenic Diet on Anxiety-like Behavior and Neuroimmune Response in C57Bl/6J Mice.
    Mohit Kumar, Babita Bhatt, Chitralekha Gusain, Nayan Mahajan, Mahendra Bishnoi.
      The ketogenic diet (KD) has been shown to reduce anxiety and enhance cognitive functions. However, the sex-specific effects of KD on anxiety-like behavior and the underlying molecular mechanisms contributing to these effects, including neuroinflammation, are unelucidated. This study investigated the sex-specific effects of KD on anxiety-like behavior and the neuroimmune response in the prefrontal cortex (PFC) and hippocampus of male and female C57BL/6J mice. Animals were fed either a control diet (CD- 17% fat, 65% carb, 18% protein) or a KD (80% fat, 5% carb, 15% protein) for four weeks. KD increased the levels of circulating β-hydroxybutyrate (BHB) both in males and females however, PFC BHB levels were found to be elevated only in KD males. However, KD did not affect the behavior of females but improved motor abilities and reduced anxiety levels in males. KD suppressed the mRNA expression of the putative microglial markers (Cd68, P2ry12, Nox2) and induced morphological changes in the male PFC microglia. A sex-specific decrease in IL1β and an increase in IL-10 levels was found in the PFC of KD males. A similar trend was observed in the hippocampus of males where KD reduced the mRNA expression of P2ry12, Il1β and cFos. Additionally, BHB increased the production of IL-10 whereas it decreased the production of IL1β by human microglia in in-vitro conditions. In summary, these results demonstrate that the anxiolytic and motor function enhancement abilities of KD are male-specific. Reduced pro-inflammatory and improved anti-inflammatory factors in the male PFC and hippocampus may underlie these effects.
    Keywords:  Anxiety; Ketone bodies; Neuroinflammation; Precision nutrition; Sex differences; β-hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.jnutbio.2024.109591
  10. Int J Mol Cell Med. 2023 ;12(2): 144-158
    Isoproterenol Alters Metabolism, Promotes Survival and Migration in 5-Fluorouracil-Treated SW480 Cells with and without Beta-hydroxybutyrate.
    Azam Shakery, Katayoun Pourvali, Ghazaleh Shimi, Hamid Zand.
      People with cancer often experience long-term physical and psychological stress, which can have a significant impact on tumor metabolism and treatment. The effects of adrenergic signaling on metabolic pathways are well known, but only a few studies have looked into the connection between this signaling and tumor metabolism. This study examined the effects of treatment with isoproterenol (Iso) alone and in combination with β-hydroxybutyrate (βHB), a mitochondrial fuel, on the metabolism, survival, and migration of SW480 colon cancer cells treated with 5-fluorouracil (5FU). The researchers measured the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) to determine the metabolic profile of these cells. They also analyzed the gene expression of PGC-1α, c-MYC, and NANOG to investigate the relationship between metabolic phenotype and stemness status. Scratch assays were used to assess cell migration. The results showed that Iso treatment increased cell viability in both SW480 and 5FU-treated SW480 cells. There was a significant decrease in ECAR and an increase in OCR after Iso treatment in both cell types. The expression of c-MYC and NANOG, genes associated with stemness, increased, while the expression of PGC-1α, a gene related to oxidative phosphorylation, decreased following Iso treatment. Iso treatment also increased the migration potential of both SW480 and 5FU-treated SW480 cells. These findings suggest that under stressful conditions, 5FU-treated colon cancer cells can utilize the oxidative phosphorylation pathway for growth and migration.
    Keywords:  5FU-treated cells; Beta-adrenergic receptor agonist; colon cancer; isoproterenol; metabolic phenotype
    DOI:  https://doi.org/10.22088/IJMCM.BUMS.12.2.144
  11. Cancer Metab. 2024 Feb 05. 12(1): 4
    Circulating metabolome landscape in Lynch syndrome.
    Tiina A Jokela, Jari E Karppinen, Minta Kärkkäinen, Jukka-Pekka Mecklin, Simon Walker, Toni T Seppälä, Eija K Laakkonen.
      Circulating metabolites systemically reflect cellular processes and can modulate the tissue microenvironment in complex ways, potentially impacting cancer initiation processes. Genetic background increases cancer risk in individuals with Lynch syndrome; however, not all carriers develop cancer. Various lifestyle factors can influence Lynch syndrome cancer risk, and lifestyle choices actively shape systemic metabolism, with circulating metabolites potentially serving as the mechanical link between lifestyle and cancer risk. This study aims to characterize the circulating metabolome of Lynch syndrome carriers, shedding light on the energy metabolism status in this cancer predisposition syndrome.This study consists of a three-group cross-sectional analysis to compare the circulating metabolome of cancer-free Lynch syndrome carriers, sporadic colorectal cancer (CRC) patients, and healthy non-carrier controls. We detected elevated levels of circulating cholesterol, lipids, and lipoproteins in LS carriers. Furthermore, we unveiled that Lynch syndrome carriers and CRC patients displayed similar alterations compared to healthy non-carriers in circulating amino acid and ketone body profiles. Overall, cancer-free Lynch syndrome carriers showed a unique circulating metabolome landscape.This study provides valuable insights into the systemic metabolic landscape of Lynch syndrome individuals. The findings hint at shared metabolic patterns between cancer-free Lynch syndrome carriers and CRC patients.
    Keywords:  Cholesterol metabolism; Circulating amino acids; DNA mismatch repair deficiency; GlycA; Hereditary cancer; Ketone bodies; Lipid metabolism; Metabolomic biomarkers
    DOI:  https://doi.org/10.1186/s40170-024-00331-9
  12. Cell Metab. 2024 Feb 06. pii: S1550-4131(24)00007-X. [Epub ahead of print]36(2): 422-437.e8
    Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding.
    Ashley S Williams, Scott B Crown, Scott P Lyons, Timothy R Koves, Rebecca J Wilson, Jordan M Johnson, Dorothy H Slentz, Daniel P Kelly, Paul A Grimsrud, Guo-Fang Zhang, Deborah M Muoio.
      Time-restricted feeding (TRF) has gained attention as a dietary regimen that promotes metabolic health. This study questioned if the health benefits of an intermittent TRF (iTRF) schedule require ketone flux specifically in skeletal and cardiac muscles. Notably, we found that the ketolytic enzyme beta-hydroxybutyrate dehydrogenase 1 (BDH1) is uniquely enriched in isolated mitochondria derived from heart and red/oxidative skeletal muscles, which also have high capacity for fatty acid oxidation (FAO). Using mice with BDH1 deficiency in striated muscles, we discover that this enzyme optimizes FAO efficiency and exercise tolerance during acute fasting. Additionally, iTRF leads to robust molecular remodeling of muscle tissues, and muscle BDH1 flux does indeed play an essential role in conferring the full adaptive benefits of this regimen, including increased lean mass, mitochondrial hormesis, and metabolic rerouting of pyruvate. In sum, ketone flux enhances mitochondrial bioenergetics and supports iTRF-induced remodeling of skeletal muscle and heart.
    Keywords:  acylcarnitines; beta-oxidation; fiber type; intermittent fasting; ketones; metabolic flux; mitochondria; proteomics; striated muscles; time-restricted feeding
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.007
  13. Proc Natl Acad Sci U S A. 2024 Feb 13. 121(7): e2310479121
    Targeting MYC induces lipid droplet accumulation by upregulation of HILPDA in clear cell renal cell carcinoma.
    Lourdes Sainero-Alcolado, Elisa Garde-Lapido, Marteinn Thor Snaebjörnsson, Sarah Schoch, Irene Stevens, María Victoria Ruiz-Pérez, Christine Dyrager, Vicent Pelechano, Håkan Axelson, Almut Schulze, Marie Arsenian-Henriksson.
      Metabolic reprogramming is critical during clear cell renal cell carcinoma (ccRCC) tumorigenesis, manifested by accumulation of lipid droplets (LDs), organelles that have emerged as new hallmarks of cancer. Yet, regulation of their biogenesis is still poorly understood. Here, we demonstrate that MYC inhibition in ccRCC cells lacking the von Hippel Lindau (VHL) gene leads to increased triglyceride content potentiating LD formation in a glutamine-dependent manner. Importantly, the concurrent inhibition of MYC signaling and glutamine metabolism prevented LD accumulation and reduced tumor burden in vivo. Furthermore, we identified the hypoxia-inducible lipid droplet-associated protein (HILPDA) as the key driver for induction of MYC-driven LD accumulation and demonstrated that conversely, proliferation, LD formation, and tumor growth are impaired upon its downregulation. Finally, analysis of ccRCC tissue as well as healthy renal control samples postulated HILPDA as a specific ccRCC biomarker. Together, these results provide an attractive approach for development of alternative therapeutic interventions for the treatment of this type of renal cancer.
    Keywords:  HILPDA; MYC; clear cell renal cell carcinoma; glutamine; lipid droplets
    DOI:  https://doi.org/10.1073/pnas.2310479121
  14. Proc Natl Acad Sci U S A. 2024 Feb 13. 121(7): e2305035121
    Brain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport.
    Johan Gustafsson, Jonathan L Robinson, Henrik Zetterberg, Jens Nielsen.
      The energy metabolism of the brain is poorly understood partly due to the complex morphology of neurons and fluctuations in ATP demand over time. To investigate this, we used metabolic models that estimate enzyme usage per pathway, enzyme utilization over time, and enzyme transportation to evaluate how these parameters and processes affect ATP costs for enzyme synthesis and transportation. Our models show that the total enzyme maintenance energy expenditure of the human body depends on how glycolysis and mitochondrial respiration are distributed both across and within cell types in the brain. We suggest that brain metabolism is optimized to minimize the ATP maintenance cost by distributing the different ATP generation pathways in an advantageous way across cell types and potentially also across synapses within the same cell. Our models support this hypothesis by predicting export of lactate from both neurons and astrocytes during peak ATP demand, reproducing results from experimental measurements reported in the literature. Furthermore, our models provide potential explanation for parts of the astrocyte-neuron lactate shuttle theory, which is recapitulated under some conditions in the brain, while contradicting other aspects of the theory. We conclude that enzyme usage per pathway, enzyme utilization over time, and enzyme transportation are important factors for defining the optimal distribution of ATP production pathways, opening a broad avenue to explore in brain metabolism.
    Keywords:  ANLS; brain metabolism; genome-scale models; mathematical modeling; metabolism
    DOI:  https://doi.org/10.1073/pnas.2305035121
  15. Front Oncol. 2023 ;13 1340386
    Sex-specific molecular differences in glioblastoma: assessing the clinical significance of genetic variants.
    Nicolina Jovanovich, Ahmed Habib, Akanksha Chilukuri, N U Farrukh Hameed, Hansen Deng, Regan Shanahan, Jeffrey R Head, Pascal O Zinn.
       Introduction: Glioblastoma multiforme (GBM) is one of the most aggressive types of brain cancer, and despite rigorous research, patient prognosis remains poor. The characterization of sex-specific differences in incidence and overall survival (OS) of these patients has led to an investigation of the molecular mechanisms that may underlie this dimorphism.
    Methods: We reviewed the published literature describing the gender specific differences in GBM Biology reported in the last ten years and summarized the available information that may point towards a patient-tailored GBM therapy.
    Results: Radiomics analyses have revealed that imaging parameters predict OS and treatment response of GBM patients in a sex-specific manner. Moreover, gender-based analysis of the transcriptome GBM tumors has found differential expression of various genes, potentially impacting the OS survival of patients in a sex-dependent manner. In addition to gene expression differences, the timing (subclonal or clonal) of the acquisition of common GBM-driver mutations, metabolism requirements, and immune landscape of these tumors has also been shown to be sex-specific, leading to a differential therapeutic response by sex. In male patients, transformed astrocytes are more sensitive to glutaminase 1 (GLS1) inhibition due to increased requirements for glutamine uptake. In female patients, GBM is more sensitive to anti-IL1β due to an increased population of circulating granulocytic myeloid-derived suppressor cells (gMDSC).
    Conclusion: Moving forward, continued elucidation of GBM sexual dimorphism will be critical in improving the OS of GBM patients by ensuring that treatment plans are structured to exploit these sex-specific, molecular vulnerabilities in GBM tumors.
    Keywords:  GBM; differences; gliomas; personalized; sex
    DOI:  https://doi.org/10.3389/fonc.2023.1340386
  16. Cancers (Basel). 2024 Jan 29. pii: 565. [Epub ahead of print]16(3):
    Patient-Derived Models of Cancer in the NCI PDMC Consortium: Selection, Pitfalls, and Practical Recommendations.
    Amber N Habowski, Deepthi P Budagavi, Sandra D Scherer, Arin B Aurora, Giuseppina Caligiuri, William F Flynn, Ellen M Langer, Jonathan R Brody, Rosalie C Sears, Giorgia Foggetti, Anna Arnal Estape, Don X Nguyen, Katerina A Politi, Xiling Shen, David S Hsu, Donna M Peehl, John Kurhanewicz, Renuka Sriram, Milagros Suarez, Sophie Xiao, Yuchen Du, Xiao-Nan Li, Nora M Navone, Estefania Labanca, Christopher D Willey.
      For over a century, early researchers sought to study biological organisms in a laboratory setting, leading to the generation of both in vitro and in vivo model systems. Patient-derived models of cancer (PDMCs) have more recently come to the forefront of preclinical cancer models and are even finding their way into clinical practice as part of functional precision medicine programs. The PDMC Consortium, supported by the Division of Cancer Biology in the National Cancer Institute of the National Institutes of Health, seeks to understand the biological principles that govern the various PDMC behaviors, particularly in response to perturbagens, such as cancer therapeutics. Based on collective experience from the consortium groups, we provide insight regarding PDMCs established both in vitro and in vivo, with a focus on practical matters related to developing and maintaining key cancer models through a series of vignettes. Although every model has the potential to offer valuable insights, the choice of the right model should be guided by the research question. However, recognizing the inherent constraints in each model is crucial. Our objective here is to delineate the strengths and limitations of each model as established by individual vignettes. Further advances in PDMCs and the development of novel model systems will enable us to better understand human biology and improve the study of human pathology in the lab.
    Keywords:  metastasis; mouse models; organoids; patient derived models of cancer; sequencing; tumor cells; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers16030565
  17. Cancer Lett. 2024 Feb 06. pii: S0304-3835(24)00089-2. [Epub ahead of print] 216696
    Palmitoylation alters LDHA activity and pancreatic cancer response to chemotherapy.
    Luojun Chen, Xiaoke Xing, Yue Zhu, Yali Chen, Huadong Pei, Qibin Song, Juanjuan Li, Pingfeng Zhang.
      Lactate dehydrogenase A (LDHA) serves as a key regulator of the Warburg Effect by catalyzing the conversion of pyruvate to lactate in the final step of glycolysis. Both the expression level and enzyme activity of LDHA are upregulated in cancers, however, the underlying mechanism remains incompletely understood. Here, we show that LDHA is post-translationally palmitoylated by ZDHHC9 at cysteine 163, which promotes its enzyme activity, lactate production, and reduces reactive oxygen species (ROS) generation. Replacement of endogenous LDHA with a palmitoylation-deficient mutant leads to reduced pancreatic cancer cell proliferation, increased T-cell infiltration, and limited tumor growth; it also affects pancreatic cancer cell response to chemotherapy. Moreover, LDHA palmitoylation is upregulated in gemcitabine resistant pancreatic cancer cells. Clinically, ZDHHC9 is upregulated in pancreatic cancer and correlated with poor prognoses for patients. Overall, our findings identify ZDHHC9-mediated palmitoylation as a positive regulator of LDHA, with potentially significant implications for cancer etiology and targeted therapy for pancreatic cancer.
    Keywords:  Gemcitabine; LDHA; Palmitoylation; Pancreatic cancer; ZDHHC9
    DOI:  https://doi.org/10.1016/j.canlet.2024.216696
  18. Am J Physiol Cell Physiol. 2024 Feb 05.
    Effect of exogenous and endogenous ketones on respiratory exchange ratio and glucose metabolism in healthy subjects.
    Rebecca Dörner, Franziska Anna Hägele, Manfred James Müller, Ulrike Seidel, Gerald Rimbach, Anja Bosy-Westphal.
      This study examined the effect of exogenous ketones (KB) on oxygen consumption (VO2), carbon dioxide production (VCO2), and glucose metabolism. The data were compared with the effects of endogenous ketonemia during both, a ketogenic diet or fasting. Eight healthy individuals (24.1 ±2.5 years, BMI 24.3 ±3.1 kg/m²) participated in a cross-over intervention study and were studied in a whole-room indirect calorimeter (WRIC) to assess macronutrient oxidation following four 24h-interventions: isocaloric controlled mixed diet (ISO), ISO supplemented with ketone salts (38.7 g beta hydroxy-butyrate/d, EXO), isocaloric ketogenic diet (KETO) and total fasting (FAST). A physical activity level of 1.65 was obtained. In addition to plasma KB, 24h C-peptide and KB excretion rates in the urine and postprandial glucose and insulin levels were measured. While 24h-KB excretion increased in response to KETO and FAST, there was a modest increase in response to EXO only (p<0.05). When compared to ISO, VO2 significantly increased in KETO (p<0.01) and EXO (p<0.001), while there was no difference in FAST. VCO2 increased in EXO but decreased in KETO (both p<0.01) and FAST (p<0.001), resulting in 24h respiratory exchange ratios (RER) of 0.828 ±0.024 (ISO) and 0.811 ±0.024 (EXO) (p<0.05). In response to EXO there were no differences in basal and postprandial glucose and insulin levels, as well as in insulin sensitivity. When compared to ISO, EXO, and KETO, FAST increased HOMA-B (all p<0.05). In conclusion, at energy balance exogenous ketone salts decreased respiratory exchange ratio without affecting glucose tolerance.
    Keywords:  glucose metabolism; insulin sensitivity; ketone salts; respiratory exchange ratio
    DOI:  https://doi.org/10.1152/ajpcell.00429.2023
  19. Cell Metab. 2024 Jan 31. pii: S1550-4131(24)00009-3. [Epub ahead of print]
    Interorgan rhythmicity as a feature of healthful metabolism.
    Joseph Bass.
      The finding that animals with circadian gene mutations exhibit diet-induced obesity and metabolic syndrome with hypoinsulinemia revealed a distinct role for the clock in the brain and peripheral tissues. Obesogenic diets disrupt rhythmic sleep/wake patterns, feeding behavior, and transcriptional networks, showing that metabolic signals reciprocally control the clock. Providing access to high-fat diet only during the sleep phase (light period) in mice accelerates weight gain, whereas isocaloric time-restricted feeding during the active period enhances energy expenditure due to circadian induction of adipose thermogenesis. This perspective focuses on advances and unanswered questions in understanding the interorgan circadian control of healthful metabolism.
    Keywords:  circadian; diabetes; epigenetics; insulin; metabolism; molecular clock; obesity; sleep; thermogenesis; transcription
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.009
  20. Int J Mol Sci. 2024 Jan 24. pii: 1433. [Epub ahead of print]25(3):
    How the 'Aerobic/Anaerobic Glycolysis' Meme Formed a 'Habit of Mind' Which Impedes Progress in the Field of Brain Energy Metabolism.
    Avital Schurr.
      The division of glycolysis into two separate pathways, aerobic and anaerobic, depending on the presence or absence of oxygen, respectively, was formulated over eight decades ago. The former ends with pyruvate, while the latter ends with lactate. Today, this division is confusing and misleading as research over the past 35 years clearly has demonstrated that glycolysis ends with lactate not only in cancerous cells but also in healthy tissues and cells. The present essay offers a review of the history of said division and the more recent knowledge that has been gained about glycolysis and its end-product, lactate. Then, it presents arguments in an attempt to explain why separating glycolysis into aerobic and anaerobic pathways persists among scientists, clinicians and teachers alike, despite convincing evidence that such division is not only wrong scientifically but also hinders progress in the field of energy metabolism.
    Keywords:  aerobic/anaerobic glycolysis; energy metabolism; habit of mind; lactate; meme; oxidative phosphorylation; pyruvate
    DOI:  https://doi.org/10.3390/ijms25031433
  21. Adv Sci (Weinh). 2024 Feb 07. e2309289
    Live Organoid Cyclic Imaging.
    David E Reynolds, Yusha Sun, Xin Wang, Phoebe Vallapureddy, Jianhua Lim, Menghan Pan, Andres Fernandez Del Castillo, Jonathan C T Carlson, Mark A Sellmyer, MacLean Nasrallah, Zev Binder, Donald M O'Rourke, Guo-Li Ming, Hongjun Song, Jina Ko.
      Organoids are becoming increasingly relevant in biology and medicine for their physiological complexity and accuracy in modeling human disease. To fully assess their biological profile while preserving their spatial information, spatiotemporal imaging tools are warranted. While previously developed imaging techniques, such as four-dimensional (4D) live imaging and light-sheet imaging have yielded important clinical insights, these technologies lack the combination of cyclic and multiplexed analysis. To address these challenges, bioorthogonal click chemistry is applied to display the first demonstration of multiplexed cyclic imaging of live and fixed patient-derived glioblastoma tumor organoids. This technology exploits bioorthogonal click chemistry to quench fluorescent signals from the surface and intracellular of labeled cells across multiple cycles, allowing for more accurate and efficient molecular profiling of their complex phenotypes. Herein, the versatility of this technology is demonstrated for the screening of glioblastoma markers in patient-derived human glioblastoma organoids while conserving their viability. It is anticipated that the findings and applications of this work can be broadly translated into investigating physiological developments in other organoid systems.
    Keywords:  biomarker discovery; bioorthogonal click-chemistry; glioblastoma; longitudinal monitoring; multiplexing; organoids
    DOI:  https://doi.org/10.1002/advs.202309289
  22. Int J Mol Sci. 2024 Jan 24. pii: 1421. [Epub ahead of print]25(3):
    Biomarkers of Response to Venetoclax Therapy in Acute Myeloid Leukemia.
    Carlos Rodríguez-Medina, Ruth Stuckey, Cristina Bilbao-Sieyro, María Teresa Gómez-Casares.
      Recent progress in the use of massive sequencing technologies has greatly enhanced our understanding of acute myeloid leukemia (AML) pathology. This knowledge has in turn driven the development of targeted therapies, such as venetoclax, a BCL-2 inhibitor approved for use in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of newly diagnosed adult patients with AML who are not eligible for intensive chemotherapy. However, a significant number of AML patients still face the challenge of disease relapse. In this review, we will explore biomarkers that may predict disease progression in patients receiving venetoclax-based therapy, considering both clinical factors and genetic changes. Despite the many advances, we conclude that the identification of molecular profiles for AML patients who will respond optimally to venetoclax therapy remains an unmet clinical need.
    Keywords:  BCL2-family proteins; acute leukemia; apoptosis; biomarkers; chemotherapy; genetics
    DOI:  https://doi.org/10.3390/ijms25031421
  23. Heliyon. 2024 Jan 15. 10(1): e23831
    Retinoblastoma vulnerability to combined de novo and salvage pyrimidine ribonucleotide synthesis pharmacologic blockage.
    Tanzina Mollick, Suhas Darekar, Basile Dalarun, Flavia Plastino, Juan Zhang, Andres Pastor Fernández, Twana Alkasalias, Helder André, Sonia Laín.
      Retinoblastoma is an eye cancer that commonly affects young children. Despite significant advances, current treatments cause side effects even when administered locally, and patients may still have to undergo enucleation. This is particularly disheartening in cases of bilateral retinoblastoma. Hence, there is an urgent need for novel therapeutic strategies. Inhibitors of the enzyme dihydroorotate dehydrogenase (DHODH), which is involved in the de novo pyrimidine ribonucleotide synthesis pathway, have proven to be effective in preclinical trials against several cancers including pediatric cancers. Here we tested whether blocking pyrimidine ribonucleotide synthesis promotes retinoblastoma cell death. Cultured retinoblastoma cell lines were treated with small molecule inhibitors of DHODH alone or in combination with inhibitors of nucleoside uptake to also block the salvage pathway for pyrimidine ribonucleotide formation. On their own, DHODH inhibitors had a moderate killing effect. However, the combination with nucleoside uptake inhibitors greatly enhanced the effect of DHODH inhibition. In addition, we observed that pyrimidine ribonucleotide synthesis blockage can cause cell death in a p53 mutant retinoblastoma cell line derived from a patient with metastasis. Explaining these results, the analysis of a published patient cohort revealed that loss of chr16q22.2 (containing the DHODH gene) is amongst the most frequent alterations in retinoblastoma and that these tumors often show gains in chromosome regions expressing pyrimidine ribonucleotide salvage factors. Furthermore, these genome alterations associate with malignancy. These results indicate that targeting pyrimidine ribonucleotide synthesis may be an effective therapeutic strategy to consider as a treatment for retinoblastoma.
    Keywords:  Apoptosis; Cell cycle; Dhodh; Genome alteration; Uridine uptake
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e23831
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