title: Increased expression of activated endothelial nitric oxide synthase contributes to antiandrogen resistance in prostate cancer cells by suppressing androgen receptor transactivation.
abstract: Development of antiandrogen-resistance in advanced prostate cancer involves multiple androgen receptor (AR)-dependent and -independent pathways. Here, we demonstrated that endothelial nitric oxide synthase (eNOS) exhibited an overexpression pattern in hormone-refractory prostate cancer and several models of advanced hormone-resistant prostate cancer. We further established a novel in vitro model of antiandrogen-resistant prostate cancer (LNCaP-BC) by long-term bicalutamide treatment. Besides antiandrogen-resistant and other enhanced malignant growth phenotypes, LNCaP-BC cells exhibited an increased activated eNOS expression and NO production, and suppressed AR transactivation status. Treatment with a NOS inhibitor L-NAME could re-sensitize the growth response to bicalutamide and enhance the AR transactivation in LNCaP-BC cells. Together, our present findings indicate that increased NO production by acquired increased expression of activated eNOS could contribute to the antiandrogen-resistant growth of prostate cancer cells, via a mechanism of NO-mediated suppression of AR activity, and also targeting eNOS could be a potential therapeutic strategy for antiandrogen-resistant prostate cancer.
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China. yushan@hkbu.edu.hk
authors.forename: Shan
authors.initials: S
authors.lastname: Yu
authors.forename: Lin
authors.initials: L
authors.lastname: Jia
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dinglan
authors.initials: D
authors.lastname: Wu
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Xu
authors.forename: Chi-Fai
authors.initials: CF
authors.lastname: Ng
authors.forename: Kenneth K W
authors.initials: KK
authors.lastname: To
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.forename: Franky L
authors.initials: FL
authors.lastname: Chan
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000726:Androgen Antagonists; D011944:Receptors, Androgen; D052250:Nitric Oxide Synthase Type III