bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2023–05–28
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. The EDA2R-NIK Axis Promotes Muscle Atrophy and Cancer Cachexia.
  2. Lactate mediated metabolic crosstalk between cancer and immune cells and its therapeutic implications.
  3. GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion.
  4. Systemic Reprogramming of Endothelial Cell Signaling in Metastasis and Cachexia.
  5. Targeting Cancer Metabolism to Improve Outcomes with Immune Checkpoint Inhibitors.
  6. Hypoxia-induced loss of SRSF2-dependent DNA methylation promotes CTCF-mediated alternative splicing of VEGFA in breast cancer.
  7. Nutrient-dependent regulation of β-cell proinsulin content.
  8. Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity.
  1. Cancer Discov. 2023 May 26. OF1
    The EDA2R-NIK Axis Promotes Muscle Atrophy and Cancer Cachexia.
      Activation of EDA2R signaling promotes the atrophy of skeletal muscle in cancer through NIK activity.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-079
  2. Front Oncol. 2023 ;13 1175532
    Lactate mediated metabolic crosstalk between cancer and immune cells and its therapeutic implications.
    Seyedeh Sahar Mortazavi Farsani, Vivek Verma.
      Metabolism is central to energy generation and cell signaling in all life forms. Cancer cells rely heavily on glucose metabolism wherein glucose is primarily converted to lactate even in adequate oxygen conditions, a process famously known as "the Warburg effect." In addition to cancer cells, Warburg effect was found to be operational in other cell types, including actively proliferating immune cells. According to current dogma, pyruvate is the end product of glycolysis that is converted into lactate in normal cells, particularly under hypoxic conditions. However, several recent observations suggest that the final product of glycolysis may be lactate, which is produced irrespective of oxygen concentrations. Traditionally, glucose-derived lactate can have three fates: it can be used as a fuel in the TCA cycle or lipid synthesis; it can be converted back into pyruvate in the cytosol that feeds into the mitochondrial TCA; or, at very high concentrations, accumulated lactate in the cytosol may be released from cells that act as an oncometabolite. In immune cells as well, glucose-derived lactate seems to play a major role in metabolism and cell signaling. However, immune cells are much more sensitive to lactate concentrations, as higher lactate levels have been found to inhibit immune cell function. Thus, tumor cell-derived lactate may serve as a major player in deciding the response and resistance to immune cell-directed therapies. In the current review, we will provide a comprehensive overview of the glycolytic process in eukaryotic cells with a special focus on the fate of pyruvate and lactate in tumor and immune cells. We will also review the evidence supporting the idea that lactate, not pyruvate, is the end product of glycolysis. In addition, we will discuss the impact of glucose-lactate-mediated cross-talk between tumor and immune cells on the therapeutic outcomes after immunotherapy.
    Keywords:  TCA cycle; Warburg effect; cancer; glycolysis; immunotherapy; lactate; metabolism; mitochondria
    DOI:  https://doi.org/10.3389/fonc.2023.1175532
  3. Diabetes. 2023 May 24. pii: db220019. [Epub ahead of print]
    GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion.
    Hui Zhang, Anny Mulya, Stephan Nieuwoudt, Bolormaa Vandanmagsar, Ruth McDowell, Elizabeth C Heintz, Elizabeth R M Zunica, J Jason Collier, Nadejda Bozadjieva-Kramer, Randy J Seeley, Christopher L Axelrod, John P Kirwan.
      Exercise is a first-line treatment for type 2 diabetes and preserves β-cell function by hitherto unknown mechanisms. We postulated that proteins from contracting skeletal muscle may act as cellular signals to regulate pancreatic β-cell function. We employed electric pulse stimulation (EPS) to induce contraction in C2C12 myotubes and found that treatment of β-cells with EPS-conditioned media (EPS-CM) enhanced glucose-stimulated insulin secretion (GSIS). Transcriptomics and subsequent targeted validation revealed Growth Differentiation Factor 15 (GDF15) as a central component of the skeletal muscle secretome. Exposure to recombinant GDF15 enhanced GSIS in cells, islets, and mice. GDF15 enhanced GSIS by upregulating the insulin secretion pathway in β-cells, which was abrogated in the presence of a GDF15 neutralizing antibody. The effect of GDF15 on GSIS was also observed in islets from GFRAL-deficient mice. Circulating GDF15 was incrementally elevated in patients with pre- and type 2 diabetes and positively associated with C-peptide in humans with overweight/obesity. Six weeks of high intensity exercise training increased circulating GDF15 concentrations, which positively correlated with improvements in β-cell function in patients with type 2 diabetes. Taken together, GDF15 can function as a contraction-induced protein that enhances GSIS through activating the canonical signaling pathway in a GFRAL-independent manner.
    DOI:  https://doi.org/10.2337/db22-0019
  4. Physiology (Bethesda). 2023 Jul 01. 38(4): 0
    Systemic Reprogramming of Endothelial Cell Signaling in Metastasis and Cachexia.
    Stephanie F Preuss, Denise Grieshober, Hellmut G Augustin.
      Proliferating cancer cells secrete a multitude of factors impacting metabolism, interorgan communication, and tumor progression. The distribution of tumor-derived factors to distant organs occurs via the circulation, which provides an extensive reactive surface lined by endothelial cells. Primary tumor-derived proteins impact cancer progression by modulating endothelial cell activation at the (pre-)metastatic niche, which affects tumor cell dissemination as well as the outgrowth of seeded metastatic cells into overt tumors. In addition, new insight indicates that endothelial cell signaling contributes to metabolic symptoms of cancer, including cancer-associated cachexia, opening a new field of vascular metabolism research. This review addresses how tumor-derived factors systemically affect endothelial cell signaling and activation and impact distant organs as well as tumor progression.
    Keywords:  angiocrine signaling; cachexia; metastasis; systemic signaling; vascular endothelium
    DOI:  https://doi.org/10.1152/physiol.00001.2023
  5. J Immunother Precis Oncol. 2023 May;6(2): 91-102
    Targeting Cancer Metabolism to Improve Outcomes with Immune Checkpoint Inhibitors.
    Zainab Fatima, Abdulrahman Abonofal, Bettzy Stephen.
      Immune checkpoint inhibitors have revolutionized the treatment paradigm of several cancers. However, not all patients respond to treatment. Tumor cells reprogram metabolic pathways to facilitate growth and proliferation. This shift in metabolic pathways creates fierce competition with immune cells for nutrients in the tumor microenvironment and generates by-products harmful for immune cell differentiation and growth. In this review, we discuss these metabolic alterations and the current therapeutic strategies to mitigate these alterations to metabolic pathways that can be used in combination with checkpoint blockade to offer a new path forward in cancer management.
    Keywords:  adenosine pathway; amino acid metabolism; glucose metabolism; immune checkpoint inhibitors; lipid metabolism
    DOI:  https://doi.org/10.36401/JIPO-22-27
  6. iScience. 2023 Jun 16. 26(6): 106804
    Hypoxia-induced loss of SRSF2-dependent DNA methylation promotes CTCF-mediated alternative splicing of VEGFA in breast cancer.
    Pooja Yadav, Anchala Pandey, Parik Kakani, Srinivas Abhishek Mutnuru, Atul Samaiya, Jharna Mishra, Sanjeev Shukla.
      Alternative splicing of vascular endothelial growth factor A (VEGFA) generates numerous isoforms with unique roles in tumor angiogenesis, and investigating the underlying mechanism during hypoxia necessitates diligent pursuance. Our research systematically demonstrated that the splicing factor SRSF2 causes the inclusion of exon-8b, leading to the formation of the anti-angiogenic VEGFA-165b isoform under normoxic conditions. Additionally, SRSF2 interacts with DNMT3A and maintains methylation on exon-8a, inhibiting CCCTC-binding factor (CTCF) recruitment and RNA polymerase II (pol II) occupancy, causing exon-8a exclusion and decreased expression of pro-angiogenic VEGFA-165a. Conversely, SRSF2 is downregulated by HIF1α-induced miR-222-3p under hypoxic conditions, which prevents exon-8b inclusion and reduces VEGFA-165b expression. Furthermore, reduced SRSF2 under hypoxia promotes hydroxymethylation on exon-8a, increasing CTCF recruitment, pol II occupancy, exon-8a inclusion, and VEGFA-165a expression. Overall, our findings unveil a specialized dual mechanism of VEGFA-165 alternative splicing, instrumented by the cross-talk between SRSF2 and CTCF, which promotes angiogenesis under hypoxic conditions.
    Keywords:  Biological sciences; Cancer; Cell biology; Molecular mechanism of gene regulation
    DOI:  https://doi.org/10.1016/j.isci.2023.106804
  7. J Biol Chem. 2023 May 18. pii: S0021-9258(23)01864-1. [Epub ahead of print] 104836
    Nutrient-dependent regulation of β-cell proinsulin content.
    Xiaoxi Xu, Anoop Arunagiri, Maroof Alam, Leena Haataja, Charles R Evans, Ivy Zhao, Roberto Castro-Gutierrez, Holger A Russ, Caroline Demangel, Ling Qi, Billy Tsai, Ming Liu, Peter Arvan.
      Insulin is made from proinsulin, but the extent to which fasting/feeding controls the homeostatically-regulated proinsulin pool in pancreatic β-cells remains largely unknown. Here, we first examined β-cell lines (INS1E and Min6, which proliferate slowly and are routinely fed fresh medium every 2-3 days) and found that the proinsulin pool size responds to each feeding within 1-2 hours; affected both by the quantity of fresh nutrients and the frequency with which they are provided. We observed no effect of nutrient feeding on the overall rate of proinsulin turnover as quantified from cycloheximide-chase experiments. We show that nutrient feeding is primarily linked to rapid de-phosphorylation of translation initiation factor eIF2α, presaging increased proinsulin levels (and thereafter, insulin levels), followed by its re-phosphorylation during the ensuing hours that correspond to a fall in proinsulin levels. The decline of proinsulin levels is blunted by the integrated stress response inhibitor, ISRIB, or by inhibition of eIF2α re-phosphorylation with a GCN2 (not PERK) kinase inhibitor. In addition, we demonstrate that amino acids contribute importantly to the proinsulin pool; mass spectrometry shows that β-cells avidly consume extracellular glutamine, serine, and cysteine. Finally, we show that in both rodent and human pancreatic islets, fresh nutrient availability dynamically increases preproinsulin, which can be quantified without pulse-labeling. Thus, the proinsulin available for insulin biosynthesis is rhythmically controlled by fasting/feeding cycles.
    Keywords:  amino acids; biosynthesis; endoplasmic reticulum; phospho-eIF2α; preproinsulin
    DOI:  https://doi.org/10.1016/j.jbc.2023.104836
  8. Cell Metab. 2023 May 17. pii: S1550-4131(23)00178-X. [Epub ahead of print]
    Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity.
    Benjamin J Jenkins, Julianna Blagih, Fernando M Ponce-Garcia, Mary Canavan, Nancy Gudgeon, Simon Eastham, David Hill, Megan M Hanlon, Eric H Ma, Emma L Bishop, April Rees, James G Cronin, Elizabeth C Jury, Sarah K Dimeloe, Douglas J Veale, Catherine A Thornton, Karen H Vousden, David K Finlay, Ursula Fearon, Gareth W Jones, Linda V Sinclair, Emma E Vincent, Nicholas Jones.
      Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 diabetes drug, is a sodium glucose co-transporter 2 (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the effects of SGLT2 inhibitors on human T cell function have not been extensively explored. Here, we show that canagliflozin-treated T cells are compromised in their ability to activate, proliferate, and initiate effector functions. Canagliflozin inhibits T cell receptor signaling, impacting on ERK and mTORC1 activity, concomitantly associated with reduced c-Myc. Compromised c-Myc levels were encapsulated by a failure to engage translational machinery resulting in impaired metabolic protein and solute carrier production among others. Importantly, canagliflozin-treated T cells derived from patients with autoimmune disorders impaired their effector function. Taken together, our work highlights a potential therapeutic avenue for repurposing canagliflozin as an intervention for T cell-mediated autoimmunity.
    Keywords:  CD4 T cell; T cell; autoimmunity; canagliflozin; gliflozins; human; immunometabolism
    DOI:  https://doi.org/10.1016/j.cmet.2023.05.001
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