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

Nam Gu Her, Seong In Jeong, Kyucheol Cho, Tae Kyu Ha, Jikhyon Han, Kyung Phil Ko, Soon Ki Park, Jin Hee Lee, Min Goo Lee, Byung Kyu Ryu, Sung Gil Chi

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1521-1535
Number of pages15
JournalCell Cycle
Volume12
Issue number10
DOIs
Publication statusPublished - 2013 May 15

Bibliographical note

Funding Information:
This work was supported in part by grants from National Research Foundation of Korea (2009-0078864 and 2009-0087099) and the National Cancer Center (0820070), Republic of Korea. The authors have no conflicts of interest to disclose.

Keywords

  • ABCA1
  • Cav1
  • PPARδ
  • Prostate cancer
  • TGF-β1

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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