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Oncology - Urology


PDGF Upregulates Mcl-1 Through Activation of ß-Catenin and HIF-1a-Dependent Signaling in Human Prostate Cancer Cells
Published: Friday, January 20, 2012
Author: Shareen Iqbal et al.

by 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

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 ß-catenin, presumably mediated by c-Abl and p68 signaling. Intriguingly, PDGF promoted formation of a nuclear transcriptional complex consisting of ß-catenin and hypoxia-inducible factor (HIF)-1a, 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.

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