title: Inhibition of NF-kappa B signaling restores responsiveness of castrate-resistant prostate cancer cells to anti-androgen treatment by decreasing androgen receptor-variant expression.
abstract: 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).
authors.affiliation: Department of Urologic Surgery, Vanderbilt Prostate Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: R
authors.initials: R
authors.lastname: Jin
authors.affiliation: Department of Urologic Surgery, Vanderbilt Prostate Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: H
authors.initials: H
authors.lastname: Yamashita
authors.affiliation: Department of Urologic Surgery, Vanderbilt Prostate Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: X
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Urologic Surgery, Vanderbilt Prostate Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Urologic Surgery, Vanderbilt Prostate Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: O E
authors.initials: OE
authors.lastname: Franco
authors.affiliation: Department of Urologic Surgery, Vanderbilt Prostate Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Urologic Surgery, Vanderbilt Prostate Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Hayward
authors.affiliation: Department of Urologic Surgery, Vanderbilt Prostate Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Matusik
mesh_terms: D000726:Androgen Antagonists / Q000008:administration & dosage* / Q000494:pharmacology; D000813:Anilides / Q000008:administration & dosage / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014105:Tosyl Compounds / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D009570:Nitriles; D011719:Pyrazines; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D000069286:Bortezomib; C053541:bicalutamide