PPARα/Bcl2 Signaling Induces Cell Apoptosis

Cancer has become the main reason of death, the global cancer incidence and mortality rate has continued to rise, due to China’s large population, there are tens of thousands of people are diagnosed with cancer every year. Therefore, intensive study of the method of pathogenesis and treatment of cancer is becoming more and more important and urgent, this will contribute to the development of more effective anti-cancer drugs.PPARα belongs to the peroxisome-proliferator-activated receptors(PPARs) family, which plays a critical role in inhibiting cell proliferation and tumorigenesis.Evasion of apoptosis is a feature of many cancer cells that is involved in overexpression of Bcl2(B-cell lymphoma 2). The Bcl2 family proteins contain pro-survival proteins(Bcl2, Bcl-xl, Mcl-1) and pro-apoptotic proteins(Bax, bad, Bim). However, it is still unclear the mechanism of the interaction of PPARα with Bcl2. Here we report that PPARα serves as an E3 ubiquitin ligase to govern Bcl2 protein stability.1. PPARα decreased Bcl2 protein levels without effect on Mcl-1, Bcl-xl and Bcl-w pro-survival protein levels The analysis of RT-PCR and real-time PCR shows that PPARα had no effect on Bcl2 gene expression.2. In vitro ubiquitination analysis was performed. The resault show that PPARα functions as a novel E3 ubiquitin ligase.quitin and PPARα induced K48-linked polyubiquitin formation. PPARα significantly induced Bcl2 ubiquitinationand C102 of PPARα was the critical enzymic site for PPARα-induced Bcl2 ubiquitination.3. Immunoprecipitation analysis shows that PPARα physically bound to Bcl2 further and then further analysis shows that C102 A mutant did not bind to Bcl2, suggesting that PPARα/C102 was critical for binding to Bcl2. Further immunoprecipitation analysis shows thatPPARα bound to BH3 domain of Bcl2.4. Further research find that lysine-22 was required for PPARα-induced Bcl2 ubiquitination and degradation. andPPARα did not induce Bcl2/K22 R mutant ubiquitination and degradation.5. PPARα significantly increased cancer cell sensitivity in response to chemotherapy drugs and activated caspase-3, PARP-1 signaling-mediated cell apoptosis. In contrast, silence of PPARα did not affect cell viability, but significantly decreased cancer cell viability in response to cytotoxic stimulation.