Inhibition of NF-kappa B signaling restores responsiveness of castrate-resistant prostate cancer cells to anti-androgen treatment by decreasing androgen receptor-variant expression

• Published in: Oncogene 2015-07, Vol.34 (28), p.3700-3710
• Main Authors: Jin, R, Yamashita, H, Yu, X, Wang, J, Franco, O E, Wang, Y, Hayward, S W, Matusik, R J
• Format: Article
• Language: English
• Subjects: 13/95; 631/67/589/466; Androgen Antagonists - administration & dosage; Androgen Antagonists - pharmacology; Androgen receptors; Androgens; Anilides - administration & dosage; Anilides - pharmacology; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Boronic Acids - administration & dosage; Boronic Acids - pharmacology; Bortezomib; Castration; Cell Biology; Cell Line, Tumor; Development and progression; Drug therapy; Gene expression; Genetic aspects; Health aspects; Human Genetics; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Neurons; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-κB protein; Nitriles - administration & dosage; Nitriles - pharmacology; Oncology; original-article; Properties; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Pyrazines - administration & dosage; Pyrazines - pharmacology; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Signal Transduction - drug effects; Splicing; Tosyl Compounds - administration & dosage; Tosyl Compounds - pharmacology; Transcription factors; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.302

Androgen receptor splicing variants (ARVs) that lack the ligand-binding domain (LBD) are associated with the development of castration-resistant prostate cancer (CRPC), including resistance to the new generation of high-affinity anti-androgens. However, the mechanism by which ARV expression is regulated is not fully understood. In this study, we show that the activation of classical nuclear factor-kappa B (NF-κB) signaling increases the expression of ARVs in prostate cancer (PCa) cells and converts androgen-sensitive PCa cells to become androgen-insensitive, whereas downregulation of NF-κB signaling inhibits ARV expression and restores responsiveness of CRPC to anti-androgen therapy. In addition, we demonstrated that combination of anti-androgen with NF-κB-targeted therapy inhibits efficiently tumor growth of human CRPC xenografts. These results indicate that induction of ARVs by activated NF-κB signaling in PCa cells is a critical mechanism by which the PCa progresses to CRPC. This has important implications as it can prolong the survival of CRPC patients by restoring the tumors to once again respond to conventional androgen-deprivation therapy (ADT).