Int J Biol Sci 2014; 10(6):627-642. doi:10.7150/ijbs.8756 This issue Cite

Research Paper

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, 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.

Citation:
Vander Griend DJ, Litvinov IV, Isaacs JT. 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. Int J Biol Sci 2014; 10(6):627-642. doi:10.7150/ijbs.8756. https://www.ijbs.com/v10p0627.htm
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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 ΔNp63-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.


Citation styles

APA
Vander Griend, D.J., Litvinov, I.V., Isaacs, J.T. (2014). 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. International Journal of Biological Sciences, 10(6), 627-642. https://doi.org/10.7150/ijbs.8756.

ACS
Vander Griend, D.J.; Litvinov, I.V.; Isaacs, J.T. 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. Int. J. Biol. Sci. 2014, 10 (6), 627-642. DOI: 10.7150/ijbs.8756.

NLM
Vander Griend DJ, Litvinov IV, Isaacs JT. 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. Int J Biol Sci 2014; 10(6):627-642. doi:10.7150/ijbs.8756. https://www.ijbs.com/v10p0627.htm

CSE
Vander Griend DJ, Litvinov IV, Isaacs JT. 2014. 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. Int J Biol Sci. 10(6):627-642.

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