Chronic acidosis rewires cancer cell metabolism through PPARα signaling
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Chronic acidosis rewires cancer cell metabolism through PPARα signaling. / Rolver, Michala G.; Holland, Lya K.K.; Ponniah, Muthulakshmi; Prasad, Nanditha S.; Yao, Jiayi; Schnipper, Julie; Kramer, Signe; Elingaard-Larsen, Line; Pedraz-Cuesta, Elena; Liu, Bin; Pardo, Luis A.; Maeda, Kenji; Sandelin, Albin; Pedersen, Stine Falsig.
I: International Journal of Cancer, Bind 152, Nr. 8, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Chronic acidosis rewires cancer cell metabolism through PPARα signaling
AU - Rolver, Michala G.
AU - Holland, Lya K.K.
AU - Ponniah, Muthulakshmi
AU - Prasad, Nanditha S.
AU - Yao, Jiayi
AU - Schnipper, Julie
AU - Kramer, Signe
AU - Elingaard-Larsen, Line
AU - Pedraz-Cuesta, Elena
AU - Liu, Bin
AU - Pardo, Luis A.
AU - Maeda, Kenji
AU - Sandelin, Albin
AU - Pedersen, Stine Falsig
N1 - Publisher Copyright: © 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - acidic microenvironment
KW - cancer metabolism
KW - fatty acid metabolism
KW - PPARα
KW - β-oxidation
U2 - 10.1002/ijc.34404
DO - 10.1002/ijc.34404
M3 - Journal article
C2 - 36533672
AN - SCOPUS:85145420386
VL - 152
JO - Acta - Unio Internationalis Contra Cancrum
JF - Acta - Unio Internationalis Contra Cancrum
SN - 0898-6924
IS - 8
ER -
ID: 333473442