Although poorly understood, androgen receptor (AR) signaling is sustained despite treatment of prostate cancer with antiandrogens and potentially underlies development of incurable castrateresistant 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 wasmediated by theDNA-bindingdomain 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.
Bibliographical noteFunding Information:
This work was financially supported by a National Cancer Institute (NCI)/NIH Research Project Grant (2RO1CA11358-06) and an NCI/NIH Exploratory/Developmental Research Grant (1R21CA178755-01) to M.T. Nevalainen. D.T. Hoang is supported by an NCI/NIH Predoctoral Individual National Research Service Award (NRSA) Fellowship (1F31CA180626- 01). A. Dagvadorj was supported by ACS-IRG (IRG-08-060-04) Research reported in this publication utilized shared resources of Kimmel Cancer Center at Thomas Jefferson University, supported by an NCI/NIH Cancer Center Core Grant (P30CA056036).