PPARα Enhances Cancer Cell Chemotherapy Sensitivity by Autophagy Induction

Abstract

PPARα (peroxisome-proliferator-activated receptor α) plays a critical role in regulation of inflammation and cancer, while the regulatory mechanism of PPARα on cancer cell autophagy is still unclear. Here we found that PPARα enhanced autophagy in HEK293T, SW480, and Hela cell lines, which was independent of PPARα transcription activity. PPARα induced antiapoptotic Bcl2 protein degradation resulting in release of the Beclin-1/VPS34 complex. Consistently, silenced PPARα reversed this event. PPARα-induced autophagy significantly inhibited tumor growth and enhanced SW480 cancer cell sensitivity to chemotherapy drugs. Moreover, PPARα agonist increased SW480 cancer cell chemotherapy sensitivity. These findings revealed a novel mechanism of PPARα/Bcl2/autophagy pathway suppressed tumor progression and enhanced chemotherapy sensitivity, which is a potential drug target for cancer treatment.

AMPK phosphorylates PPARδ to mediate its stabilization, inhibit glucose and glutamine uptake and colon tumor growth

“…Peroxisome-proliferator-activated receptors (PPARs) contain PPARα, PPARγ, and PPARδ (30)(31)(32)(33)(34).…”

“…PPARs contain PPARα, PPARγ, and PPARδ ( 30 , 31 , 32 , 33 , 34 ). PPARδ can be activated by the fatty acids or fatty-acid derivatives, which is involved in the mucosal inflammation and malignant transformation ( 26 ).…”

PPAR-α Modulators as Current and Potential Cancer Treatments

“…Moreover, WY14643 is able to increase chemosensitivity via affecting the transcriptional activity of glucose transporter-1, and inhibit mTOR pathway, leading to apoptosis of cancer cells ( 38 ). With regards to colorectal carcinoma SW480 cells, another PPAR-α agonist, clofibrate, significantly suppresses tumor proliferation and sensitizes SW480 cells to chemotherapy drugs in a PPAR-α-dependent manner that induces antiapoptotic Bcl2 protein degradation and promotes autophagy ( 83 ). Furthermore, PPAR-α transgenic mice with increased expression of DNMT1 and PRMT6 have higher susceptibility to the development of colorectal cancer, which can be reduced by the activation of PPAR-α with the application of fenofibrate ( 39 ).…”

Nuclear Receptor PPARα as a Therapeutic Target in Diseases Associated with Lipid Metabolism Disorders

“…Concerning colorectal carcinoma cells, an additional PPARα agonist, clofibrate, profoundly inhibits tumor proliferation. It sensitizes colorectal carcinoma cells to chemotherapy drugs in a PPARα-dependent manner, leading to the degradation of the antiapoptotic Bcl2 protein and the induction of autophagy [94]. Furthermore, several reports suggest PPARα ligands as potential chemopreventive agents in colon carcinogenesis.…”