Inhibition of Stat5a/b Enhances Proteasomal Degradation of Androgen Receptor Liganded by Antiandrogens in Prostate Cancer. Mol Cancer Ther 2015 Mar;14(3):713-26
Date
01/02/2015Pubmed ID
25552366Pubmed Central ID
PMC4456253DOI
10.1158/1535-7163.MCT-14-0819Scopus ID
2-s2.0-84960924230 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
Although poorly understood, androgen receptor (AR) signaling is sustained despite treatment of prostate cancer with antiandrogens and potentially underlies development of incurable castrate-resistant prostate cancer. However, therapies targeting the AR signaling axis eventually fail when prostate cancer progresses to the castrate-resistant stage. Stat5a/b, a candidate therapeutic target protein in prostate cancer, synergizes with AR to reciprocally enhance the signaling of both proteins. In this work, we demonstrate that Stat5a/b sequesters antiandrogen-liganded (MDV3100, bicalutamide, flutamide) AR in prostate cancer cells and protects it against proteasomal degradation in prostate cancer. Active Stat5a/b increased nuclear levels of both unliganded and antiandrogen-liganded AR, as demonstrated in prostate cancer cell lines, xenograft tumors, and clinical patient-derived prostate cancer samples. Physical interaction between Stat5a/b and AR in prostate cancer cells was mediated by the DNA-binding domain of Stat5a/b and the N-terminal domain of AR. Moreover, active Stat5a/b increased AR occupancy of the prostate-specific antigen promoter and AR-regulated gene expression in prostate cancer cells. Mechanistically, both Stat5a/b genetic knockdown and antiandrogen treatment induced proteasomal degradation of AR in prostate cancer cells, with combined inhibition of Stat5a/b and AR leading to maximal loss of AR protein and prostate cancer cell viability. Our results indicate that therapeutic targeting of AR in prostate cancer using antiandrogens may be substantially improved by targeting of Stat5a/b.
Author List
Hoang DT, Gu L, Liao Z, Shen F, Talati PG, Koptyra M, Tan SH, Ellsworth E, Gupta S, Montie H, Dagvadorj A, Savolainen S, Leiby B, Mirtti T, Merry DE, Nevalainen MTMESH terms used to index this publication - Major topics in bold
Androgen AntagonistsAndrogens
Anilides
Benzamides
Cell Line, Tumor
Cell Survival
Flutamide
Gene Expression Regulation, Neoplastic
Humans
Ligands
Male
Nitriles
Phenylthiohydantoin
Promoter Regions, Genetic
Prostate-Specific Antigen
Prostatic Neoplasms, Castration-Resistant
Proteasome Endopeptidase Complex
Receptors, Androgen
STAT5 Transcription Factor
Signal Transduction
Tosyl Compounds
Tumor Suppressor Proteins
