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Carcinogenesis Advance Access published online on January 3, 2008
Carcinogenesis, doi:10.1093/carcin/bgm259
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Androgen Receptor Regulates CD168 Expression and Signaling in Prostate Cancer

Shi-Lung Lin*, Donald Chang, Angela Chiang and Shao-Yao Ying*

Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A

* Requests for reprints: Shao-Yao Ying or Shi-Lung Lin, Department of Cell and Neurobiology, Keck School of Medicine, BMT-403, University of Southern California, 1333 San Pablo Street, Los Angeles, CA 90033. Phone: 1-323-442-1856; Fax: 1-323-442-3466; E-mail: sying{at}usc.edu or lins{at}usc.edu

Dysregulation of the androgen receptor (AR) and its signaling in the prostate often occurs during normal aging or after androgen ablation, consequently leading to the development of hormone-refractory prostate cancer (HRPC). Hyaluronan (HA) plays an important role in this transformation of androgen-independent cancer. Previous studies have shown that activation of the receptor for HA-mediated motility, CD168, was correlated with the Gleason's score, cancer stage, transformation, and metastasis in over 90% of HRPC patients. However, the relationship between loss of AR dependency and HA-mediated CD168 signaling remains unclear. We report here that AR regulates normal CD168 expression and its downstream signaling in androgen-dependent prostatic epithelial cell lines. Furthermore, we observed that the concurrent treatments of HA and dihydrotestosterone (DHT), a native androgen, significantly promoted the tumorigenecity of androgen-dependent prostate cancer cell lines which showed elevated rates of cell proliferation, invasion, and metastasis to the human bone marrow endothelial cell (hBMEC) layer. Inhibition of CD168-downstream Rho-activated kinases (ROCK) completely prevented this type of tumorigenecity. These findings suggest that the interaction of androgen and AR is essential for regulating HA-mediated cancer progression via the CD168/ROCK signal transduction pathway and also indicate that the loss of AR regulation not only cause CD168 over-expression, but it also activates HA-mediated CD168 signaling in malignant cancer progression and metastasis of HRPC.

Key Words: hormone-refractory prostate cancer (HRPC) • androgen-independent cancer transformation • cancer relapse • androgen receptor (AR) • extracellular matrix (ECM) • hyaluronan (HA) • CD168 (RHAMM) • Rho-activated protein kinase (ROCK/ROK) • aging

Received July 5, 2007; revised November 5, 2007; accepted November 8, 2007.


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