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International Journal Of Bilogical Sciences

.: Home > International Journal Of Bilogical Sciences > 2014 > Volume 10 Number 6 > Donald J. Vander Griend1,3,Ivan V. Litvinov1,2, and John T. Isaacs1,2,3

Conversion of Androgen Receptor Signaling From a Growth Suppressor in Normal Prostate Epithelial Cells to an Oncogene in Prostate Cancer Cells Involves a Gain of Function in c-Myc Regulation

Donald J. Vander Griend1,3,Ivan V. Litvinov1,2, and John T. Isaacs1,2,3
1. Chemical Therapeutics Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. 2. Cellular and Molecular Medicine Graduate Program at Johns Hopkins. 3. The Brady Urological Institute, Johns Hopkins.  Corresponding author: John T. Isaacs, Ph.D., The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans St., Baltimore, MD 21231, 410-614-6321,
Abstract :

In normal prostate, androgen-dependent androgen receptor (AR) signaling within prostate stromal cells induces their secretion of paracrine factors, termed “andromedins” which stimulate growth of the epithelial cells. The present studies demonstrate that androgen-dependent andromedin-driven growth stimulation is counter-balanced by androgen-induced AR signaling within normal adult prostate epithelial cells resulting in terminal G0 growth arrest coupled with terminal differentiation into ∆Np63-negative, PSA-expressing secretory luminal cells. This cell autonomous AR-driven terminal differentiation requires DNA-binding of the AR protein, is associated with decreases in c-Myc m-RNA and protein, are coupled with increases in p21, p27, and SKP-2 protein expression, and does not require functional p53. These changes result in down-regulation of Cyclin D1 protein and RB phosphoryation. shRNA knockdown documents that neither RB, p21, p27 alone or in combination are required for such AR-induced G0 growth arrest. Transgenic expression of a constitutive vector to prevent c-Myc down-regulation overrides AR-mediated growth arrest in normal prostate epithelial cells, which documents that AR-induced c-Myc down-regulation is critical in terminal growth arrest of normal prostate epithelial cells. In contrast, in prostate cancer cells, androgen-induced AR signaling paradoxically up-regulates c-Myc expression and stimulates growth as documented by inhibition of both of these responses following exposure to the AR antagonist, bicalutamide. These data document that AR signaling is converted from a growth suppressor in normal prostate epithelial cells to an oncogene in prostate cancer cells during prostatic carcinogenesis and that this conversion involves a gain of function for regulation of c-Myc expression.

Keywords :
Androgen Receptor, Human Prostate Cancer, Tumor Suppressor, Oncogene, MYC

Date Deposited : 12 Feb 2016 09:19

Last Modified : 12 Feb 2016 09:19

Official URL:

Volume 10, Number 6, - 2014 , ISSN 1449-2288

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