PDGF upregulates Mcl-1 through activation of β-catenin and HIF-1α-dependent signaling in human prostate cancer cells

Shareen Iqbal, Shumin Zhang, Adel Driss, Zhi Ren Liu, Hyeong Reh Choi Kim, Yanru Wang, Chad Ritenour, Haiyen E. Zhau, Omer Kucuk, Leland W.K. Chung, Daqing Wu

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Background: Aberrant platelet derived growth factor (PDGF) signaling has been associated with prostate cancer (PCa) progression. However, its role in the regulation of PCa cell growth and survival has not been well characterized. Methodology/Principal Findings: Using experimental models that closely mimic clinical pathophysiology of PCa progression, we demonstrated that PDGF is a survival factor in PCa cells through upregulation of myeloid cell leukemia-1 (Mcl-1). PDGF treatment induced rapid nuclear translocation of β-catenin, presumably mediated by c-Abl and p68 signaling. Intriguingly, PDGF promoted formation of a nuclear transcriptional complex consisting of β-catenin and hypoxia-inducible factor (HIF)-1α, and its binding to Mcl-1 promoter. Deletion of a putative hypoxia response element (HRE) within the Mcl-1 promoter attenuated PDGF effects on Mcl-1 expression. Blockade of PDGF receptor (PDGFR) signaling with a pharmacological inhibitor AG-17 abrogated PDGF induction of Mcl-1, and induced apoptosis in metastatic PCa cells. Conclusions/Significance: Our study elucidated a crucial survival mechanism in PCa cells, indicating that interruption of the PDGF-Mcl-1 survival signal may provide a novel strategy for treating PCa metastasis.

Original languageEnglish (US)
Article numbere30764
JournalPloS one
Volume7
Issue number1
DOIs
StatePublished - Jan 20 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Iqbal, S., Zhang, S., Driss, A., Liu, Z. R., Kim, H. R. C., Wang, Y., Ritenour, C., Zhau, H. E., Kucuk, O., Chung, L. W. K., & Wu, D. (2012). PDGF upregulates Mcl-1 through activation of β-catenin and HIF-1α-dependent signaling in human prostate cancer cells. PloS one, 7(1), [e30764]. https://doi.org/10.1371/journal.pone.0030764