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