Silencing of PMEPA1 accelerates the growth of prostate cancer cells through AR, NEDD4 and PTEN
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Hua Li1, Ahmed A. Mohamed1, Shashwat Sharad1, Elizabeth Umeda1, Yingjie Song1, Denise Young1, Gyorgy Petrovics1, David G. McLeod1,2, Isabell A. Sesterhenn3, Taduru Sreenath1, Albert Dobi1, Shiv Srivastava1
1Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
2Urology Service, Walter Reed National Military Medical Center, Bethesda, MD 20814, USA
3Joint Pathology Center, Silver Spring, MD 20910, USA
Albert Dobi, e-mail: [email protected]
Shiv Srivastava, e-mail: [email protected]
Keywords: prostate cancer, PMEPA1, androgen receptor, NEDD4, enzalutamide
Received: December 31, 2014 Accepted: March 09, 2015 Published: March 30, 2015
Androgen Receptor (AR) is the male hormone receptor and a nuclear transcription factor which plays a central role in the growth of normal and malignant prostate gland. Our earlier studies defined a mechanistic model for male hormone dependent regulation of AR protein levels in prostate cancer (CaP) cells through a negative feed-back loop between AR and PMEPA1, an androgen induced NEDD4 E3 ubiquitin ligase binding protein. This report focuses on the impact of PMEPA1 silencing on CaP biology. PMEPA1 knockdown accelerated the growth of CaP tumor cells in athymic nude mice. In cell culture models knockdown of PMEPA1 resulted in resistance to AR inhibitors enzalutamide and bicalutamide. While, AR protein down regulation by NEDD4 was PMEPA1 dependent, we also noted a PMEPA1 independent downregulation of PTEN by NEDD4. In a subset of human CaP, decreased PMEPA1 mRNA expression significantly correlated with increased levels of AR transcription target PSA, as a surrogate for elevated AR. This study highlights that silencing of PMEPA1 accelerates the growth of CaP cells through AR, NEDD4 and PTEN. Thus, the therapeutic restoration of PMEPA1 represents a promising complementary strategy correcting for AR and PTEN defects in CaP. Statement of significance: Here we define that silencing of PMEPA1 facilitates the growth of CaP cells and modulates AR through NEDD4 and PTEN. The restoration of PMEPA1 represents a promising complementary therapeutic strategy correcting for AR and PTEN defects.
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