Fujimoto Naohiro
   Department   School of Medicine  Urology, Clinical Medical Sciences
   Position  
Article types journal article
Language English
Peer review Peer reviewed
Title Potential Role for YB-1 in Castration-Resistant Prostate Cancer and Resistance to Enzalutamide Through the Androgen Receptor V7.
Journal Formal name:Journal of the National Cancer Institute
Abbreviation:J Natl Cancer Inst
ISSN code:14602105/00278874
Domestic / ForeginForegin
Volume, Issue, Page 108(7),djw005頁
Author and coauthor Shiota Masaki, Fujimoto Naohiro, Imada Kenjiro, Yokomizo Akira, Itsumi Momoe, Takeuchi Ario, Kuruma Hidetoshi, Inokuchi Junichi, Tatsugami Katsunori, Uchiumi Takeshi, Oda Yoshinao, Naito Seiji
Publication date 2016/07
Summary BACKGROUND:Although androgen deprivation therapy for advanced prostate cancer initially exerts excellent anticancer effects, most prostate cancer treated with androgen deprivation therapy eventually recurs as castration-resistant prostate cancer (CRPC). Although aberrant kinase activation has been proposed as a mechanism of castration resistance, comprehensive kinase profiles in CRPC remain unknown. Therefore, we aimed to elucidate the kinome in CRPC as well as the role of key molecules.METHODS:We utilized a kinome array in androgen-dependent LNCaP and castration-resistant CxR cells. The effect of Y-box binding protein-1 (YB-1) on androgen receptor (AR) expression was examined by quantitative polymerase chain reaction and western blot analysis. The association between polymorphisms in the YB-1 gene determined by genotyping and YB-1 expression evaluated by immunohistochemistry in prostate cancer tissues, as well as outcome in metastatic prostate cancer, were investigated by the Cochran-Armitage test and the Cox proportional hazards model, respectively. All statistical tests were two-sided.RESULTS:One hundred fifty-six of 180 kinase phosphorylation sites, including ERK and RSK, were activated in CRPC cells, leading to increased phosphorylation of YB-1, which is a key molecule in the progression to CRPC. YB-1 signaling regulated AR V7 expression, and YB-1 inhibition augmented the anticancer effect of enzalutamide. Moreover, polymorphism (rs12030724) in the YB-1 gene affected YB-1 expression in 93 prostate cancer tissues (YB-1 positive rate; 14.3% in TT, 40.0% in AT, and 52.9% in AA, P = .04) and associated with probability of progression in 104 metastatic prostate cancer case patients (AT/TT vs AA, hazard ratio = 0.49, 95% confidence interval = 0.32 to 0.77, P = .001).CONCLUSIONS:YB-1 appears to be a promising target to inhibit the development of castration resistance, even at the AR variant-expressing stage. Polymorphism in the YB-1 gene may be a promising predictive
DOI 10.1093/jnci/djw005
PMID 26857528