Potential Role for YB-1 in Castration-Resistant Prostate Cancer and Resistance to Enzalutamide Through the Androgen Receptor V7

JNCI: Journal of the National Cancer Institute, Jul 2016

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.

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Potential Role for YB-1 in Castration-Resistant Prostate Cancer and Resistance to Enzalutamide Through the Androgen Receptor V7

JNCI J Natl Cancer Inst ( Potential Role for YB-1 in Castration-Resistant Prostate Cancer and Resistance to Enzalutamide Through the Androgen Receptor V7 Masaki Shiota 0 1 2 3 4 Naohiro Fujimoto 0 1 2 3 4 Kenjiro Imada 0 1 2 3 4 Akira Yokomizo 0 1 2 3 4 Momoe Itsumi 0 1 2 3 4 Ario Takeuchi 0 1 2 3 4 Hidetoshi Kuruma 0 1 2 3 4 Junichi Inokuchi 0 1 2 3 4 0 and Laboratory Medicine (TU), Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan; Department of Urology, School of Medicine, University of 1 Affiliations of authors: Department of Urology (MS , KI, AY, MI, AT, JI, KT, SN) , Department of Anatomic Pathology (KI, YO), and Department of Clinical Chemistry 2 Katsunori Tatsugami , Takeshi Uchiumi, Yoshinao Oda, Seiji Naito 3 The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions , please 4 Occupational and Environmental Health , Kitakyushu , Japan ( NF); Department of Urology, School of Medicine, Jikei University , Tokyo , Japan , HK 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 and western blot analysis. The association between polymorphisms in tYhBe-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. Enzalutamide - 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 theYB-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 0.7P7 ,= .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 thYeB-1 gene may be a promising predictive biomarker in hormonal therapy. For recurrent or advanced prostate cancer, androgen deprivation and exhibit an apparently good response to ADT, most event-u therapy (ADT) is a milestone therapy1(). Although most prostate ally recur in a castration-resistant fashion during ADT, and they cancers are initially dependent on androgens for tumor growth are defined as castration-resistant prostate cancer (CRP2C)). T(o date, several molecular mechanisms involved in the progr-es CxR cells were homogenized in lysis buffer. Serially diluted cell sion to castration resistance are known, including androgen lysates (1:1, 1:2, 1:4, 1:8) were spotted onto glass slides in eight receptor A(R) amplification and overexpressionA,R mutations, replicates with an arrayer. Signals from slides stained with cant survival benefit for patients with CRPC6).( However, these agents can exert only a modest survival benefit, which can be attributed to de novo expression of the AR varian7t–( 11 ). Y-box binding protein-1 (YB-1) is known to function in the nucleus as a transcription factor that binds Y-bo x′-A(5TTGG-3′), as well as in the cytoplasm as a RNA-binding factor involved online) for more details. in RNA splicing to modulate the expression of its target genes ( 12,13 ). Numerous studies showed that YB-1 was overexpressed and involved in treatment resistance in various cancer1s2(,13). We previously showed that YB-1 upregulated after androgen ablation 1(4) was overexpressed in highly malignant potential prostate cancer and promoted castration resistance via AR o-ver (available online). expression (15,16); inversely, YB-1 suppression augmented ce-l lular sensitivity to castration as well as to enzalutam1i7d)e. ( Mouse Castration Model Xenograft experiments in mice were performed as previously described (27). Please see theSupplementary Methods(available Antibodies, Reagents, Plasmid, and siRNA These materials are described in theSupplementary Methods Intracellular signaling pathways mediate various extra-cel Western Blot Analysis, and Cytotoxicity Analysis splicing, and tran (...truncated)


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Shiota, Masaki, Fujimoto, Naohiro, Imada, Kenjiro, Yokomizo, Akira, Itsumi, Momoe, Takeuchi, Ario, Kuruma, Hidetoshi, Inokuchi, Junichi, Tatsugami, Katsunori, Uchiumi, Takeshi, Oda, Yoshinao, Naito, Seiji. Potential Role for YB-1 in Castration-Resistant Prostate Cancer and Resistance to Enzalutamide Through the Androgen Receptor V7, JNCI: Journal of the National Cancer Institute, 2016, Volume 108, Issue 7, DOI: 10.1093/jnci/djw005