bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2024‒08‒11
eleven papers selected by
Brett Chrest, East Carolina University
  1. The polyunsaturated fatty acid docosahexaenoic affects mitochondrial function in prostate cancer cells.
  2. Ketogenic diet but not free-sugar restriction alters glucose tolerance, lipid metabolism, peripheral tissue phenotype, and gut microbiome: RCT.
  3. Contemporary Management of Acute Myeloid Leukemia: A Review.
  4. Aspartate in tumor microenvironment and beyond: Metabolic interactions and therapeutic perspectives.
  5. Synergistic Effects of Glutamine Deprivation and Metformin in Acute Myeloid Leukemia.
  6. Ketone bodies rescue T cell impairments induced by low glucose availability.
  7. Glutamine withdrawal leads to the preferential activation of lipid metabolism in metastatic colorectal cancer.
  8. Hypoxanthine in the microenvironment can enable thiopurine resistance in acute lymphoblastic leukemia.
  9. Sphingosine-1 phosphate receptor 1 (S1PR1) expression maintains stemness of acute myeloid leukemia stem cells.
  10. Engineering new-to-nature biochemical conversions by combining fermentative metabolism with respiratory modules.
  11. Association of serum lactate dehydrogenase with prognosis and tumor metabolism in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab therapy.
  1. Cancer Metab. 2024 Aug 07. 12(1): 24
    The polyunsaturated fatty acid docosahexaenoic affects mitochondrial function in prostate cancer cells.
    Guilherme Henrique Tamarindo, Caroline Fidalgo Ribeiro, Alana Della Torre Silva, Alex Castro, Ícaro Putinhon Caruso, Fátima Pereira Souza, Sebastião Roberto Taboga, Massimo Loda, Rejane Maira Góes.
      BACKGROUND: Prostate cancer (PCa) shows a rewired metabolism featuring increased fatty acid uptake and synthesis via de novo lipogenesis, both sharply related to mitochondrial physiology. The docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid (PUFA) that exerts its antitumoral properties via different mechanisms, but its specific action on mitochondria in PCa is not clear. Therefore, we investigated whether the DHA modulates mitochondrial function in PCa cell lines.METHODS: Here, we evaluated mitochondrial function of non-malignant PNT1A and the castration-resistant (CRPC) prostate 22Rv1 and PC3 cell lines in response to DHA incubation. For this purpose, we used Seahorse extracellular flux assay to assess mitochondria function, [14C]-glucose to evaluate its oxidation as well as its contribution to fatty acid synthesis, 1H-NMR for metabolite profile determination, MitoSOX for superoxide anion production, JC-1 for mitochondrial membrane polarization, mass spectrometry for determination of phosphatidylglycerol levels and composition, staining with MitoTracker dye to assess mitochondrial morphology under super-resolution in addition to Transmission Electron Microscopy, In-Cell ELISA for COX-I and SDH-A protein expression and flow cytometry (Annexin V and 7-AAD) for cell death estimation.
    RESULTS: In all cell lines DHA decreased basal respiratory activity, ATP production, and the spare capacity in mitochondria. Also, the omega-3 induced mitochondrial hyperpolarization, ROS overproduction and changes in membrane phosphatidylglycerol composition. In PNT1A, DHA led to mitochondrial fragmentation and it increased glycolysis while in cancer cells it stimulated glucose oxidation, but decreased de novo lipogenesis specifically in 22Rv1, indicating a metabolic shift. In all cell lines, DHA modulated several metabolites related to energy metabolism and it was incorporated in phosphatidylglycerol, a precursor of cardiolipin, increasing the unsaturation index in the mitochondrial membrane. Accordingly, DHA triggered cell death mainly in PNT1A and 22Rv1.
    CONCLUSION: In conclusion, mitochondrial metabolism is significantly affected by the PUFA supplementation to the point that cells are not able to proliferate or survive under DHA-enriched condition. Moreover, combination of DHA supplementation with inhibition of metabolism-related pathways, such as de novo lipogenesis, may be synergistic in castration-resistant prostate cancer.
    Keywords:  Docosahexaenoic acid; Lipid metabolism; Mitochondria; Omega-3 polyunsaturated fatty acids; Prostate cancer cells
    DOI:  https://doi.org/10.1186/s40170-024-00348-0
  2. Cell Rep Med. 2024 Aug 01. pii: S2666-3791(24)00381-1. [Epub ahead of print] 101667
    Ketogenic diet but not free-sugar restriction alters glucose tolerance, lipid metabolism, peripheral tissue phenotype, and gut microbiome: RCT.
    Aaron Hengist, Russell G Davies, Jean-Philippe Walhin, Jariya Buniam, Lucy H Merrell, Lucy Rogers, Louise Bradshaw, Alfonso Moreno-Cabañas, Peter J Rogers, Jeff M Brunstrom, Leanne Hodson, Luc J C van Loon, Wiley Barton, Ciara O'Donovan, Fiona Crispie, Orla O'Sullivan, Paul D Cotter, Kathryn Proctor, James A Betts, Françoise Koumanov, Dylan Thompson, Javier T Gonzalez.
      Restricted sugar and ketogenic diets can alter energy balance/metabolism, but decreased energy intake may be compensated by reduced expenditure. In healthy adults, randomization to restricting free sugars or overall carbohydrates (ketogenic diet) for 12 weeks reduces fat mass without changing energy expenditure versus control. Free-sugar restriction minimally affects metabolism or gut microbiome but decreases low-density lipoprotein cholesterol (LDL-C). In contrast, a ketogenic diet decreases glucose tolerance, increases skeletal muscle PDK4, and reduces AMPK and GLUT4 levels. By week 4, the ketogenic diet reduces fasting glucose and increases apolipoprotein B, C-reactive protein, and postprandial glycerol concentrations. However, despite sustained ketosis, these effects are no longer apparent by week 12, when gut microbial beta diversity is altered, possibly reflective of longer-term adjustments to the ketogenic diet and/or energy balance. These data demonstrate that restricting free sugars or overall carbohydrates reduces energy intake without altering physical activity, but with divergent effects on glucose tolerance, lipoprotein profiles, and gut microbiome.
    Keywords:  body fat; diet; energy balance; energy intake; ketogenic; lipoprotein; low carbohydrate; metabolism; physical activity; sugar
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101667
  3. JAMA Oncol. 2024 Aug 08.
    Contemporary Management of Acute Myeloid Leukemia: A Review.
    Sangeetha Venugopal, Mikkael A Sekeres.
      Importance: Acute myeloid leukemia (AML) is a clonal hematopoietic cancer that disrupts normal hematopoiesis, ultimately leading to bone marrow failure and death. The annual incidence rate of AML is 4.1 per 100 000 people in the US and is higher in patients older than 65 years. Acute myeloid leukemia includes numerous subgroups with heterogeneous molecular profiles, treatment response, and prognosis. This review discusses the evidence supporting frontline therapies in AML, the major principles that guide therapy, and progress with molecularly targeted therapy.Observations: Acute myeloid leukemia is a genetically complex, dynamic disease. The most commonly altered genes include FLT3, NPM1, DNMT3A, IDH1, IDH2, TET2, RUNX1, NRAS, and TP53. The incidence of these alterations varies by patient age, history of antecedent hematologic cancer, and previous exposure to chemotherapy and/or radiotherapy for any cancer. Since 2010, molecular data have been incorporated into AML prognostication, gradually leading to incorporation of targeted therapies into the initial treatment approach of induction chemotherapy and subsequent management. The first molecularly targeted inhibitor, midostaurin, was approved to treat patients with AML with FLT3 variants in 2017. Since then, the understanding of the molecular pathogenesis of AML has expanded, allowing the identification of additional potential targets for drug therapy, treatment incorporation of molecularly targeted therapies (midostaurin, gilteritinib, and quizartinib targeting FLT3 variants; ivosidenib and olutasidenib targeting IDH1 variants, and enasidenib targeting IDH2), and identification of rational combination regimens. The approval of hypomethylating agents combined with venetoclax has revolutionized the therapy of AML in older adults, extending survival over monotherapy. Additionally, patients are now referred for hematopoietic cell transplant on a more rational basis.
    Conclusions and Relevance: In the era of genomic medicine, AML treatment is customized to the patient's comorbidities and AML genomic profile.
    DOI:  https://doi.org/10.1001/jamaoncol.2024.2662
  4. Biochim Biophys Acta Mol Basis Dis. 2024 Aug 05. pii: S0925-4439(24)00444-7. [Epub ahead of print]1870(8): 167451
    Aspartate in tumor microenvironment and beyond: Metabolic interactions and therapeutic perspectives.
    Julian Wong Soon, Maria Antonietta Manca, Agnieszka Laskowska, Julia Starkova, Katerina Rohlenova, Jakub Rohlena.
      Aspartate is a proteinogenic non-essential amino acid with several essential functions in proliferating cells. It is mostly produced in a cell autonomous manner from oxalacetate via glutamate oxalacetate transaminases 1 or 2 (GOT1 or GOT2), but in some cases it can also be salvaged from the microenvironment via transporters such as SLC1A3 or by macropinocytosis. In this review we provide an overview of biosynthetic pathways that produce aspartate endogenously during proliferation. We discuss conditions that favor aspartate uptake as well as possible sources of exogenous aspartate in the microenvironment of tumors and bone marrow, where most available data have been generated. We highlight metabolic fates of aspartate, its various functions, and possible approaches to target aspartate metabolism for cancer therapy.
    Keywords:  Amino acid; Biosynthesis; Cancer; Leukemia; Malate-aspartate shuttle; Respiratory chain; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167451
  5. Curr Med Sci. 2024 Aug 03.
    Synergistic Effects of Glutamine Deprivation and Metformin in Acute Myeloid Leukemia.
    Tong-Yuan Liu, Xing Fu, Ying Yang, Jia Gu, Min Xiao, Deng-Ju Li.
      OBJECTIVE: The metabolic reprogramming of acute myeloid leukemia (AML) cells is a compensatory adaptation to meet energy requirements for rapid proliferation. This study aimed to examine the synergistic effects of glutamine deprivation and metformin exposure on AML cells.METHODS: SKM-1 cells (an AML cell line) were subjected to glutamine deprivation and/or treatment with metformin or bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES, a glutaminase inhibitor) or cytarabine. Cell viability was detected by Cell Counting Kit-8 (CCK-8) assay, and cell apoptosis and reactive oxygen species (ROS) by flow cytometry. Western blotting was conducted to examine the levels of apoptotic proteins, including cleaved caspase-3 and poly(ADP-ribose) polymerase (PARP). Moreover, the human long noncoding RNA (lncRNA) microarray was used to analyze gene expression after glutamine deprivation, and results were confirmed with quantitative RT-PCR (qRT-PCR). The expression of metallothionein 2A (MT2A) was suppressed using siRNA. Cell growth and apoptosis were further detected by CCK-8 assay and flow cytometry, respectively, in cells with MT2A knockdown.
    RESULTS: Glutamine deprivation or treatment with BPTES inhibited cell growth and induced apoptosis in SKM-1 cells. The lncRNA microarray result showed that the expression of MT family genes was significantly upregulated after glutamine deprivation. MT2A knockdown increased apoptosis, while proliferation was not affected in SKM-1 cells. In addition, metformin inhibited cell growth and induced apoptosis in SKM-1 cells. Both glutamine deprivation and metformin enhanced the sensitivity of SKM-1 cells to cytarabine. Furthermore, the combination of glutamine deprivation with metformin exhibited synergistic antileukemia effects on SKM-1 cells.
    CONCLUSION: Targeting glutamine metabolism in combination with metformin is a promising new therapeutic strategy for AML.
    Keywords:  acute myeloid leukemia; glutamine; metallothionein; metformin
    DOI:  https://doi.org/10.1007/s11596-024-2913-z
  6. Eur J Nutr. 2024 Aug 06.
    Ketone bodies rescue T cell impairments induced by low glucose availability.
    Arianna Ferrari, Jessica Filoni, Carla Di Dedda, Lorenzo Piemonti, Paolo Monti.
      PURPOSE: Ketogenic diets are proposed as a therapeutic approach for type 1 and type 2 diabetes due to their low glucose intake. However, their potential effects on the immune system need investigation. This study aims to explore how glucose concentration and beta-hydroxybutyrate (BHB) impact T cell phenotype, metabolism, and function, with a focus on systemic inflammatory response (T2D) and autoimmunity (T1D).METHODS: T cells from healthy donors were cultured in vitro under varying glucose concentrations with or without BHB. Flow cytometry was employed to analyze changes in T cell phenotype, while proliferation was evaluated through a CFSE dilution assay. Additionally, we used a novel flow cytometry method allowing a direct assessment of T cell metabolism.
    RESULTS: Culturing T cells in low glucose concentrations revealed their dependency on glucose metabolism, leading to reduced proliferation rates, overexpression of exhaustion markers and increased susceptibility to Treg suppression and the influence of immune-modulating drugs such as rapamycin, FK506, and MMF. Notably, T cells cultured in low glucose concentrations increased the expression of BDH1 to utilize BHB as an alternative fuel source. Finally, the addition of BHB to the culture effectively rescued T cell impairments caused by insufficient glucose levels.
    CONCLUSIONS: T cells display limited capacity to adapt to low glucose levels, resulting in profound functional impairment. However, T cell functions can be efficiently recovered by the presence of 2mM BHB.
    Keywords:  Immunometabolism; Ketogenic diet; T cells; Type 1 diabetes
    DOI:  https://doi.org/10.1007/s00394-024-03469-w
  7. Transl Oncol. 2024 Aug 06. pii: S1936-5233(24)00205-5. [Epub ahead of print]48 102078
    Glutamine withdrawal leads to the preferential activation of lipid metabolism in metastatic colorectal cancer.
    Aliye Ezgi Güleç Taşkıran, Diren Arda Karaoğlu, Cemil Can Eylem, Çağdaş Ermiş, İsmail Güderer, Emirhan Nemutlu, Seçil Demirkol Canlı, Sreeparna Banerjee.
      INTRODUCTION: Glutamine is a non-essential amino acid that is critical for cell growth. However, the differential metabolism of l-glutamine in metastatic versus primary colorectal cancer (CRC) has not been evaluated adequately.MATERIALS AND METHODS: Differential expression of glutamine-related genes was determined in primary versus metastatic CRC. Univariate Cox regression and hierarchical clustering were used to generate a gene signature for prognostication. Untargeted metabolomics and 18O based fluxomics were used to identify differential metabolite levels and energy turnover in the paired primary (SW480) and metastatic (SW620) CRC cells. Western blot and qRT-PCR were used to validate differential gene expression. Subcellular localization of E-cadherin was determined by immunocytochemistry. Lipid droplets were visualized with Nile Red.
    RESULTS: The GO term "Glutamine metabolism" was significantly enriched in metastatic versus primary tumors. Supporting this, SW620 cells showed decreased membrane localization of E-cadherin and increased motility upon l-Glutamine withdrawal. A glutamine related signature associated with worse prognosis was identified and validated in multiple datasets. A fluxomics assay revealed a slower TCA cycle in SW480 and SW620 cells upon l-Glutamine withdrawal. SW620 cells, however, could maintain high ATP levels. Untargeted metabolomics indicated the preferential metabolism of fatty acids in SW620 but not SW480 cells. Lipids were mainly obtained from the environment rather than by de novo synthesis.
    CONCLUSIONS: Metastatic CRC cells can display aberrant glutamine metabolism. We show for the first time that upon l-glutamine withdrawal, SW620 (but not SW480) cells were metabolically plastic and could metabolize lipids for survival and cellular motility.
    Keywords:  Colorectal cancer; L-Glutamine; Lipid metabolism; Metabolic plasticity
    DOI:  https://doi.org/10.1016/j.tranon.2024.102078
  8. Front Oncol. 2024 ;14 1440650
    Hypoxanthine in the microenvironment can enable thiopurine resistance in acute lymphoblastic leukemia.
    Xiaohong Wang, Jason Ostergaard, Jongseok Kang, Grace Sagong, Rachel Twite, Andrea Vargas-Morales, Peter M Gordon.
      Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, with relapse being a major obstacle to successful treatment. Our understanding of the mechanisms driving chemotherapy resistance and ultimately relapse in leukemia remains incomplete. Herein, we investigate the impact of the tumor microenvironment on leukemia cell drug responses using human plasma-like media (HPLM), designed to mimic physiological conditions more accurately ex vivo. We demonstrate that while most chemotherapeutics maintain an efficacy in HPLM comparable to standard tissue culture media, the thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) exhibit significantly reduced potency and efficacy against both B- and T- leukemia cells in HPLM. By merging our understanding of thiopurines' mechanism of action with the metabolites supplemented in HPLM compared to standard media, we proposed and subsequently validated the hypothesis that hypoxanthine, a purine derivative, is responsible for conferring resistance to the thiopurines. Importantly, the concentration of hypoxanthine required for resistance is comparable to physiological levels found in vivo, supporting clinical relevance. Our findings demonstrate the utility of a more physiologic media in identifying and characterizing mechanisms by which the microenvironment can enable resistance. Understanding such interactions may inform strategies to overcome drug resistance and improve therapeutic outcomes in pediatric leukemia.
    Keywords:  acute lymphoblastic leukemia; chemoresistance; microenvironment; thiopurine compounds; tissue culture media
    DOI:  https://doi.org/10.3389/fonc.2024.1440650
  9. Cancer Lett. 2024 Aug 05. pii: S0304-3835(24)00553-6. [Epub ahead of print] 217158
    Sphingosine-1 phosphate receptor 1 (S1PR1) expression maintains stemness of acute myeloid leukemia stem cells.
    Yu-Qing Wang, Yue Ren, Robert Peter Gale, Li-Ting Niu, Xiao-Jun Huang.
      Acute myeloid leukemia (AML) arises from leukemia stem cells (LSCs) and is maintained by cells which have acquired features of stemness. We compared transcription profiles of AML cells with/without stem cell features defined as in vitro clonogenicity and serial engraftment in immune-deficient mice xenograft model. We used multi-parameter flow cytometry (MPFC) to separate CD34+ bone marrow-derived leukemia cells into sphingosine-1 phosphate receptor 1 (S1PR1)+ and S1PR1- fractions. Cells in the S1PR1+ fraction demonstrated significantly higher clonogenicity and higher engraftment potential compared with those in the S1PR1- fraction. In contrast, CD34+ bone marrow cells from normal samples showed reduced clonogenicity in the S1PR1+ fraction compared with the S1PR1- fraction. Inhibition of S1PR1 expression in an AML cell line reduced the colony-forming potential of KG1 cells. Transcriptomic analyses and rescue experiments indicated PI3K/AKT pathway and MYBL2 are downstream mediators of S1PR1-associated stemness. These findings implicate S1PR1 as a functional biomarker of LSCs and suggest its potential as a therapeutic target in AML treatment.
    Keywords:  Acute myeloid leukemia; Leukemia stem cells; S1PR1
    DOI:  https://doi.org/10.1016/j.canlet.2024.217158
  10. Nat Commun. 2024 Aug 07. 15(1): 6725
    Engineering new-to-nature biochemical conversions by combining fermentative metabolism with respiratory modules.
    Helena Schulz-Mirbach, Jan Lukas Krüsemann, Theofania Andreadaki, Jana Natalie Nerlich, Eleni Mavrothalassiti, Simon Boecker, Philipp Schneider, Moritz Weresow, Omar Abdelwahab, Nicole Paczia, Beau Dronsella, Tobias J Erb, Arren Bar-Even, Steffen Klamt, Steffen N Lindner.
      Anaerobic microbial fermentations provide high product yields and are a cornerstone of industrial bio-based processes. However, the need for redox balancing limits the array of fermentable substrate-product combinations. To overcome this limitation, here we design an aerobic fermentative metabolism that allows the introduction of selected respiratory modules. These can use oxygen to re-balance otherwise unbalanced fermentations, hence achieving controlled respiro-fermentative growth. Following this design, we engineer and characterize an obligate fermentative Escherichia coli strain that aerobically ferments glucose to stoichiometric amounts of lactate. We then re-integrate the quinone-dependent glycerol 3-phosphate dehydrogenase and demonstrate glycerol fermentation to lactate while selectively transferring the surplus of electrons to the respiratory chain. To showcase the potential of this fermentation mode, we direct fermentative flux from glycerol towards isobutanol production. In summary, our design permits using oxygen to selectively re-balance fermentations. This concept is an advance freeing highly efficient microbial fermentation from the limitations imposed by traditional redox balancing.
    DOI:  https://doi.org/10.1038/s41467-024-51029-x
  11. Surg Today. 2024 Aug 04.
    Association of serum lactate dehydrogenase with prognosis and tumor metabolism in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab therapy.
    Katsuya Toshida, Shinji Itoh, Takeo Toshima, Shohei Yoshiya, Yuki Bekki, Takuma Izumi, Norifumi Iseda, Yuki Nakayama, Takuma Ishikawa, Tomoharu Yoshizumi.
      PURPOSE: Treatment outcomes are predicted by analyzing peripheral blood markers such as serum lactate dehydrogenase (LDH). We conducted this study to investigate whether serum LDH levels can predict the prognosis of patients treated with atezolizumab plus bevacizumab (ATZ/BEV) therapy for hepatocellular carcinoma (HCC) and whether LDH levels correlate with metabolic changes.METHODS: We enrolled 66 HCC patients treated with ATZ/BEV. Based on the change in serum LDH levels before and after treatment, the patients were divided into two groups, and the prognosis of each group was examined. Moreover, the association of LDH levels with tumor metabolism was analyzed by fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT).
    RESULTS: There were 32 patients categorized as the LDH-decrease group. Kaplan-Meier survival analysis indicated worse progression-free survival (PFS) in the LDH-increase group than in the LDH-decrease group (p = 0.0029). Multivariate analysis showed that an increase in the LDH level was an independent risk factor for worse PFS (p = 0.0045). The baseline LDH level correlated significantly with a high maximum standardized uptake value of 18F-FDG, according to the PET/CT findings. Transcriptomic analyses of specimens resected after ATZ/BEV therapy showed downregulated mitochondria-related pathways.
    CONCLUSION: Serum LDH levels are a potential prognostic marker and an indicator of tumor metabolism.
    Keywords:  Atezolizumab plus bevacizumab; Hepatocellular carcinoma; Lactate dehydrogenase; Tumor metabolism
    DOI:  https://doi.org/10.1007/s00595-024-02914-x
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