PPAR? Enhances Cancer Cell Warburg Effect By Inhibition Of Mitophagy

Cancer cells exhibit the ability to maintain the abnormal mitochondrial accumulation by mitophagy inhibition resulting in increased aerobic glycolysis(Warburg effect),while the mechanism is still unclear.Here we found that PPAR? contains LIR(LC3 interacting region)motif that bound to LC3(the microtubule-associated protein 1 light chain 3).Immunoprecipitation analysis showed that PPAR?-LIR domain bound to LC3 B.In addition,the LIR motif of PPAR? was required for promoting glucose uptake in cancer cells,which was related to the inhibition of PPAR?-mediated mitophagy-associated protein expressions.In contrast,PPAR? shRNA silence or PPAR?/Y42 R mutant alleviated this event.PPAR? mediated mitophagy inhibition of cancer cells leading to increased tumor growth.The specific findings are as follows:1.PPAR? contains LIR motif that bound to LC3 B,while the mutant PPAR?/Y42 R reduced this event.2.PPAR? not PPAR?/Y42 R mutant increased glucose uptake,consumption and lactate release.3.PPAR? not PPAR?/Y42 R mutant increased the levels of COX?,Tom20 and mitochondrial DNA,suggesting that PPAR? inhibited mitophagy.4.Western blot analysis revealed that PPAR? inhibited the expressions of mitophagy-associated protein.In contrast,PPAR? shRNA silence or PPAR?/Y42 R mutant alleviated this event.5.The assay of soft agar and xenograft tumor model showed that PPAR? not the PPAR?/Y42 R mutant promoted cancer cell proliferation and tumor growth,which was consistent with the inhibition of PPAR?-LIR on mitophagy-associated protein expressions in tumor tissues.These findings revealed a novel mechanism of PPAR?-mediated inhibition of mitophagy resulting in Warburg effect and tumor growth.