PPARα induces cell apoptosis by destructing Bcl2

// Jiaming Gao 1, 2, * , Qian Liu 1, * , Ying Xu 2 , Xin Gong 2 , Runyun Zhang 2 , Chenglin Zhou 3 , Zhaoliang Su 4 , Jianhua Jin 1 , Haifeng Shi 2 , Juanjuan Shi 2 , Yongzhong Hou 1, 2 1 Department of Oncology, The Affiliated Wujin People's Hospital, Jiangsu University, Changzhou, Jiangsu Province, China 2 Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu Province, China 3 Jiangsu Taizhou People's Hospital, Jiangsu Province, China 4 Department of Immunology & Laboratory Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China * These authors have contributed equally to this work Correspondence to: Juanjuan Shi, e-mail: sjj@ujs.edu.cn Yongzhong Hou, e-mail: houyz@ujs.edu.cn Keywords: ubiquitination, degradation, apoptosis, PPARα, Bcl2 Received: June 24, 2015 Accepted: October 01, 2015 Published: November 09, 2015 ABSTRACT PPARα 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 PPARα serves as an E3 ubiquitin ligase to govern Bcl2 protein stability. PPARα physically bound to Bcl2 protein. In this process, PPARα/C102 was critical for PPARα binding to BH3 domain of Bcl2, subsequently, PPARα transferred K48-linked polyubiquitin to lysine-22 site of Bcl2 resulting in its ubiquitination and proteasome-dependent degradation. Importantly, overexpression of PPARα enhanced cancer cell chemotherapy sensitivity. In contrast, silenced PPARα decreased this event. These findings revealed a novel mechanism of PPARα governed endogenous Bcl2 protein stability leading to reduced cancer cell chemoresistance, which provides a potential drug target for cancer treatment.