PPARδ promotes oncogenic redirection of TGF-β1 signaling through the activation of the ABCA1-Cav1 pathway

TGF-β1 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-β1 function remains largely undefined. Here, we demonstrate that PPARδ is a direct t...

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Bibliographic Details
Published in:Cell cycle (Georgetown, Tex.) Tex.), 2013-05, Vol.12 (10), p.1521-1535
Main Authors: Her, Nam-Hu, Jeong, Seong-In, Cho, Kyucheol, Ha, Tae-Kyu, Han, Jykhyon, Ko, Kyung-Phil, Park, Soon-Ki, Lee, Jin-Hee, Lee, Min-Goo, Ryu, Byung-Kyu, Chi, Sung-Gil
Format: Article
Language:English
Subjects:
ABCA1
Animals
ATP Binding Cassette Transporter 1 - antagonists & inhibitors
ATP Binding Cassette Transporter 1 - genetics
ATP Binding Cassette Transporter 1 - metabolism
Cav1
Caveolin 1 - antagonists & inhibitors
Caveolin 1 - genetics
Caveolin 1 - metabolism
Cell Line, Tumor
Cell Movement
Humans
Male
Mice
Mice, Nude
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3 - metabolism
PPAR delta - antagonists & inhibitors
PPAR delta - genetics
PPAR delta - metabolism
PPARδ
prostate cancer
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
RNA Interference
RNA, Messenger - metabolism
RNA, Small Interfering - metabolism
Signal Transduction - drug effects
Smad Proteins - antagonists & inhibitors
Smad Proteins - genetics
Smad Proteins - metabolism
TGF-β1
Transforming Growth Factor beta1 - metabolism
Transforming Growth Factor beta1 - pharmacology
Transplantation, Heterologous
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Summary:TGF-β1 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-β1 function remains largely undefined. Here, we demonstrate that PPARδ is a direct transcription target of TGF-β1 and plays a critical role in oncogenic redirection of TGF-β1 signaling. Blockade of PPARδ induction enhances tumor cell response to TGF-β1-mediated growth inhibition, while its activation promotes TGF-β1-induced tumor growth, migration and invasion. PPARδ-mediated switch of TGF-β1 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-β1 activation of the PPARδ-ABCA1-Cav1 pathway facilitates degradation of TGF-β receptors (TβRs) and attenuates Smad but enhances ERK response to TGF-β1. Expression of PPARδ 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 PPARδ is a transcription target of TGF-β1 and contributes to the oncogenic conversion of TGF-β1 function through activation of the ABCA1-Cav1-TβR signaling axis.
ISSN:1538-4101
1551-4005
DOI:10.4161/cc.24636