Androgen receptor regulates CD168 expression and signaling in prostate cancer

• Published in: Carcinogenesis (New York) Vol. 29; no. 2; pp. 282 - 290
• Main Authors: Lin, Shi-Lung, Chang, Donald, Chiang, Angela, Ying, Shao-Yao
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.02.2008; Oxford Publishing Limited (England)
• Subjects: Animals; Biological and medical sciences; Bone Marrow Cells - metabolism; Carcinogenesis, carcinogens and anticarcinogens; Cell Line, Tumor; Dihydrotestosterone - pharmacology; Extracellular Matrix Proteins - biosynthesis; Extracellular Matrix Proteins - physiology; Gene Expression Regulation, Neoplastic; Gynecology. Andrology. Obstetrics; Humans; Hyaluronan Receptors - biosynthesis; Hyaluronan Receptors - physiology; Male; Male genital diseases; Medical sciences; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness; Neoplasm Metastasis; Nephrology. Urinary tract diseases; Prostatic Neoplasms - metabolism; Receptors, Androgen - physiology; Signal Transduction; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Signal transduction; Urinary system disease; Prostate disease; Androgen receptor; Malignant tumor; Male genital diseases; Prostate cancer; Cancer; Hormonal receptor
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgm259

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 hyaluronan-mediated motility, CD168, was correlated with the Gleason’s score, cancer stage, transformation and metastasis in >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 (AD) prostatic epithelial cell lines. Furthermore, we observed that the concurrent treatments of HA and dihydrotestosterone (DHT), a native androgen, significantly promoted the tumorigenicity of AD prostate cancer cell lines, which showed elevated rates of cell proliferation, invasion and metastasis to the human bone marrow endothelial cell layer. Inhibition of CD168 downstream Rho-activated protein kinases completely prevented this type of tumorigenicity. 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 causes CD168 overexpression but it also activates HA-mediated CD168 signaling in malignant cancer progression and metastasis of HRPC.