PPAR? promotes oncogenic redirection of TGF-?1 signaling through the activation of the ABCA1-Cav1 pathway.

ABSTRACT: TGF-?1 plays biphasic functions in prostate tumorigenesis, inhibiting cell growth at early stages but promoting malignant progression at later stages. However, the molecular basis for the oncogenic conversion of TGF-?1 function remains largely undefined. Here, we demonstrate that PPAR? is a direct transcription target of TGF-?1 and plays a critical role in oncogenic redirection of TGF-?1 signaling. Blockade of PPAR? induction enhances tumor cell response to TGF-?1-mediated growth inhibition, while its activation promotes TGF-?1-induced tumor growth, migration and invasion. PPAR?-mediated switch of TGF-?1 function is associated with down- and upregulation of Smad and ERK signaling, respectively, and tightly linked to its function to activate ABCA1 cholesterol transporter followed by caveolin-1 (Cav1) induction. Intriguingly, TGF-?1 activation of the PPAR?-ABCA1-Cav1 pathway facilitates degradation of TGF-? receptors (T?Rs) and attenuates Smad but enhances ERK response to TGF-?1. Expression of PPAR? and Cav1 is tightly correlated in both prostate tissues and cell lines and significantly higher in cancer vs. normal tissues. Collectively, our study shows that PPAR? is a transcription target of TGF-?1 and contributes to the oncogenic conversion of TGF-?1 function through activation of the ABCA1-Cav1-T?R signaling axis.

SUBMITTER: Her NG 

PROVIDER: S-EPMC3680532 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature