PPAR delta promotes oncogenic redirection of TGF-beta 1 signaling through the activation of the ABCA1-Cav1 pathway

초록

TGF-beta 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-beta 1 function remains largely undefined. Here, we demonstrate that PPAR is a direct transcription target of TGF-beta 1 and plays a critical role in oncogenic redirection of TGF-beta 1 signaling. Blockade of PPAR induction enhances tumor cell response to TGF-beta 1-mediated growth inhibition, while its activation promotes TGF-beta 1-induced tumor growth, migration and invasion. PPAR-mediated switch of TGF-beta 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-beta 1 activation of the PPAR-ABCA1-Cav1 pathway facilitates degradation of TGF-beta receptors (TRs) and attenuates Smad but enhances ERK response to TGF-beta 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-beta 1 and contributes to the oncogenic conversion of TGF-beta 1 function through activation of the ABCA1-Cav1-TR signaling axis.

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