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.
Highlights
IntroductionApoptosis (programmed cell death) plays a critical role in maintenance of normal tissues homeostasis by elimination of the unwanted or damaged cells from organisms [1]
Apoptosis plays a critical role in maintenance of normal tissues homeostasis by elimination of the unwanted or damaged cells from organisms [1]
Evasion of apoptosis is a feature of many cancer cells that is involved in overexpression of Bcl2 (B-cell lymphoma 2) [2]
Summary
Apoptosis (programmed cell death) plays a critical role in maintenance of normal tissues homeostasis by elimination of the unwanted or damaged cells from organisms [1]. Bcl is a proto-oncogene to inhibit cell apoptosis in the tumor development. The Bcl family proteins contain pro-survival proteins (Bcl, Bcl-xl, Mcl1) and pro-apoptotic proteins (Bax, bad, Bim) [2, 3]. Bcl constrains the pro-apoptotic proteins (Bax, Bak) to maintain the mitochondrial integrity and cell survival. Cytotoxic stimuli (chemotherapy or radiotherapy) activate pro-apoptotic proteins and induce cell apoptosis [1]. Deregulated Bcl expression leads to impaired apoptosis that is a critical step in tumorigenesis, it is still unclear the mechanism to govern Bcl protein stability
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