PPARα induces cell apoptosis by destructing Bcl2

PPAR alpha belongs to the peroxisome-proliferator-activated receptors (PPARs) family, which plays a critical role in inhibiting cell proliferation and tumorigenesis, while the molecular mechanism is still unclear. Here we report that PPAR alpha serves as an E3 ubiquitin ligase to govern Bcl2 protein stability. PPAR alpha physically bound to Bcl2 protein. In this process, PPAR alpha/C102 was critical for PPAR alpha binding to BH3 domain of Bcl2, subsequently, PPAR alpha transferred K48-linked polyubiquitin to lysine-22 site of Bcl2 resulting in its ubiquitination and proteasome-dependent degradation. Importantly, overexpression of PPAR alpha enhanced cancer cell chemotherapy sensitivity. In contrast, silenced PPAR alpha decreased this event. These findings revealed a novel mechanism of PPAR alpha governed endogenous Bcl2 protein stability leading to reduced cancer cell chemoresistance, which provides a potential drug target for cancer treatment.