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.
Written by:
Iqbal S, Zhang S, Driss A, Liu ZR, Kim HR, Wang Y, Ritenour C, Zhau HE, Kucuk O, Chung LW, Wu D. Are you the author?
Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Reference: PLoS One. 2012;7(1):e30764. Epub 2012 Jan 20.
PubMed Abstract
PMID: 22276222
UroToday.com Investigational Urology Section
