Tubulin-Targeting Chemotherapy Impairs Androgen Receptor Activity in Prostate Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 20; pp. 7992 - 8002
• Main Authors: ZHU, Meng-Lei, HORBINSKI, Craig M, GARZOTTO, Mark, QIAN, David Z, BEER, Tomasz M, KYPRIANOU, Natasha
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-10-2010
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - toxicity; Biological and medical sciences; Cell Line, Tumor; Docetaxel; Gene Expression Regulation, Neoplastic; Gynecology. Andrology. Obstetrics; Humans; Male; Male genital diseases; Medical sciences; Microarray Analysis; Mitoxantrone - therapeutic use; Mitoxantrone - toxicity; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Prostate-Specific Antigen - genetics; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptors, Androgen - drug effects; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm - genetics; RNA, Neoplasm - isolation & purification; Taxoids - therapeutic use; Taxoids - toxicity; Tubulin - drug effects; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Urinary system disease; Prostate disease; Targeting; Malignant tumor; Biological activity; Chemotherapy; Target; Treatment; Tubulin; Androgen receptor; Male genital diseases; Prostate cancer; Cancer; Hormonal receptor
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-0585

Recent insights into the regulation of the androgen receptor (AR) activity led to novel therapeutic targeting of AR function in prostate cancer patients. Docetaxel is an approved chemotherapy for treatment of castration-resistant prostate cancer; however, the mechanism underlying the action of this tubulin-targeting drug is not fully understood. This study investigates the contribution of microtubules and the cytoskeleton to androgen-mediated signaling and the consequences of their inhibition on AR activity in human prostate cancer. Tissue microarrays from docetaxel-treated and untreated prostate cancer patients were comparatively analyzed for prostate-specific antigen (PSA) and AR immunoreactivity. The AR transcriptional activity was determined in prostate cancer cells in vitro, based on PSA mRNA expression and the androgen response element reporter activity. The interaction of AR with tubulin was examined by immunoprecipitation and immunofluorescence. Treatment of prostate cancer patients with docetaxel led to a significant translocation of AR. In untreated specimens, 50% prostate tumor cells exhibited nuclear accumulation of AR, compared with docetaxel-treated tumors that had significantly depleted nuclear AR (38%), paralleled by an increase in cytosolic AR. AR nuclear localization correlated with PSA expression. In vitro, exposure of prostate cancer cells to paclitaxel (1 μmol/L) or nocodazole (5 μg/mL) inhibited androgen-dependent AR nuclear translocation by targeting AR association with tubulin. Introduction of a truncated AR indicated the requirement of the NH(2)-terminal domain for AR-tubulin interaction. Our findings show that in addition to blocking cell division, docetaxel impairs AR signaling, evidence that enables new insights into the therapeutic efficacy of microtubule-targeting drugs in prostate cancer.