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, email@example.com.
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.
Androgen Receptor, Human Prostate Cancer, Tumor Suppressor, Oncogene, MYC
Date Deposited : 12 Feb 2016 09:19
Official URL: http://www.ijbs.com/v10i6
Last Modified : 12 Feb 2016 09:19
Volume 10, Number 6, - 2014 , ISSN 1449-2288
Full Text Original