Androgen suppresses proliferation of castration‐resistant LNCaP 104‐R2 prostate cancer cells through androgen receptor, Skp2, and c‐Myc
Open Access
- 22 July 2011
- journal article
- Published by Wiley in Cancer Science
- Vol. 102 (11), 2022-2028
- https://doi.org/10.1111/j.1349-7006.2011.02043.x
Abstract
Androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side‐effects, including increased risk of cardiovascular diseases. To study if termination of long‐term androgen ablation and restoration of testosterone levels could suppress the growth of relapsed hormone‐refractory prostate tumors, we implanted testosterone pellets in castrated nude mice carrying androgen receptor (AR)‐positive LNCaP 104‐R2 cells, which relapsed from androgen‐dependent LNCaP 104‐S cells after long‐term androgen deprivation. 104‐R2 tumor xenografts regressed after testosterone pellets were implanted. Of 33 tumors, 24 adapted to elevation of testosterone level and relapsed as androgen‐insensitive tumors. Relapsed tumors (R2Ad) expressed less AR and prostate‐specific antigen. We then studied the molecular mechanism underlying the androgenic regulation of prostate cancer cell proliferation. Androgen suppresses proliferation of 104‐R2 by inducing G1 cell cycle arrest through reduction of S‐phase kinase‐associated protein 2 (Skp2) and c‐Myc, and induction of p27Kip1. 104‐R2 cells adapted to androgen treatment and the adapted cells, R2Ad, were androgen‐insensitive cells with a slower growth rate and low protein level of AR, high levels of c‐Myc and Skp2, and low levels of p27Kip1. Nuclear AR and prostate‐specific antigen expression is present in 104‐R2 cells but not R2Ad cells when androgen is absent. Overexpression of AR in R2Ad cells regenerated an androgen‐repressed phenotype; knockdown of AR in 104‐R2 cells generated an androgen‐insensitive phenotype. Overexpression of Skp2 and c‐Myc in 104‐R2 cells blocked the growth inhibition caused by androgens. We concluded that androgens cause growth inhibition in LNCaP 104‐R2 prostate cancer cells through AR, Skp2, and c‐Myc. (Cancer Sci 2011; 102: 2022–2028)Keywords
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