Chronic acidosis rewires cancer cell metabolism through PPARα signaling
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The mechanisms linking tumor microenvironment acidosis to disease progression are not understood. Here, we used mammary, pancreatic, and colon cancer cells to show that adaptation to growth at an extracellular pH (pHe) mimicking acidic tumor niches is associated with upregulated net acid extrusion capacity and elevated intracellular pH at physiological pHe, but not at acidic pHe. Using metabolic profiling, shotgun lipidomics, imaging and biochemical analyses, we show that the acid adaptation-induced phenotype is characterized by a shift toward oxidative metabolism, increased lipid droplet-, triacylglycerol-, peroxisome content and mitochondrial hyperfusion. Peroxisome proliferator-activated receptor-α (PPARA, PPARα) expression and activity are upregulated, at least in part by increased fatty acid uptake. PPARα upregulates genes driving increased mitochondrial and peroxisomal mass and β-oxidation capacity, including mitochondrial lipid import proteins CPT1A, CPT2 and SLC25A20, electron transport chain components, peroxisomal proteins PEX11A and ACOX1, and thioredoxin-interacting protein (TXNIP), a negative regulator of glycolysis. This endows acid-adapted cancer cells with increased capacity for utilizing fatty acids for metabolic needs, while limiting glycolysis. As a consequence, the acid-adapted cells exhibit increased sensitivity to PPARα inhibition. We conclude that PPARα is a key upstream regulator of metabolic changes favoring cancer cell survival in acidic tumor niches.
Originalsprog | Engelsk |
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Tidsskrift | International Journal of Cancer |
Vol/bind | 152 |
Udgave nummer | 8 |
Antal sider | 17 |
ISSN | 0020-7136 |
DOI | |
Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
Danish Cancer Society, Grant/Award Numbers: A12359, R124‐A7929‐15‐S2; Department of Biology, University of Copenhagen, Grant/Award Number: BIO Elite PhD Scholarship; Independent Research Fund Denmark, Grant/Award Numbers: 6108‐00542B, 0135‐00139B; Novo Nordisk Fonden, Grant/Award Number: NNF19OC0058262 Funding information + 3 − + + e i +
Funding Information:
This work was supported by the Danish Cancer Society (Albin Sandelin, Stine F. Pedersen, #A12359), the Novo Nordisk Foundation (Albin Sandelin, Stine F. Pedersen, #NNF19OC0058262), Independent Research Fund Denmark (Stine F. Pedersen, #0135‐00139B), Independent Research Fund Denmark (Kenji Maeda, #6108‐00542B), Danish Cancer Society (Kenji Maeda, #R124‐A7929‐15‐S2) and a BIO Elite PhD scholarship from the Department of Biology, University of Copenhagen, to Michala G. Rolver.
Publisher Copyright:
© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
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