The curcumin analog ca27 down-regulates androgen receptor through an oxidative stress mediated mechanism in human prostate cancer cells

• Published in: The Prostate Vol. 72; no. 6; pp. 612 - 625
• Main Authors: Fajardo, Alexandra M., MacKenzie, Debra A., Ji, Ming, Deck, Lorraine M., Jagt, David L. Vander, Thompson, Todd A., Bisoffi, Marco
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-05-2012
• Subjects: androgen receptor; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Curcumin - analogs & derivatives; Curcumin - pharmacology; curcumin analog; Down-Regulation - drug effects; Humans; Male; oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; prostate cancer; Prostatic Neoplasms - metabolism; Reactive Oxygen Species - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.21464

BACKGROUND
The androgen receptor (AR) plays a critical role in prostate cancer development and progression. Therefore, the inhibition of AR function is an established therapeutic intervention. Since the expression of the AR is retained and often increased in progressive disease, AR protein down‐regulation is a promising therapeutic approach against prostate cancer. We show here that the curcumin analog 27 (ca27) down‐regulates AR expression in several prostate cancer cell lines.
METHODS
ca27 at low micromolar concentrations was tested for its effect on AR expression, AR activation, and induction of oxidative stress in human LNCaP, C4‐2, and LAPC‐4 prostate cancer cells.
RESULTS
ca27 induced the down‐regulation of AR protein expression in LNCaP, C4‐2, and LAPC‐4 cells within 12 hr. Further, ca27 led to the rapid induction of reactive oxygen species (ROS). To further support this finding, ca27 treatment led to the activation of the cellular redox sensor NF‐E2‐related factor 2 (Nrf2) and the induction of the Nrf2‐regulated genes NAD(P)H quinone oxidoreductase 1 and aldoketoreductase 1C1. We show that ROS production preceded AR protein loss and that ca27‐mediated down‐regulation of the AR was attenuated by the antioxidant, N‐acetyl cysteine.
CONCLUSIONS
ca27 induces ROS and mediates AR protein down‐regulation through an oxidative stress mechanism of action. Our results suggest that ca27 represents a novel agent for the elucidation of mechanisms of AR down‐regulation, which could lead to effective new anti‐androgenic strategies for the treatment of advanced prostate cancer. Prostate 72:612–625, 2012. © 2011 Wiley Periodicals, Inc.