YB-1 在去势抵抗性前列腺癌和恩杂鲁胺耐药中的潜在作用：通过雄激素受体 V7。

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

机构信息

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 and Laboratory Medicine (TU), Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan ; Department of Urology, School of Medicine, University of Occupational and Environmental Health , Kitakyushu , Japan (NF); Department of Urology, School of Medicine, Jikei University , Tokyo , Japan (HK).

出版信息

J Natl Cancer Inst. 2016 Feb 8;108(7). doi: 10.1093/jnci/djw005. Print 2016 Jul.

DOI:10.1093/jnci/djw005

PMID:26857528

Abstract

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 biomarker in hormonal therapy.

摘要

背景

尽管雄激素剥夺疗法（androgen deprivation therapy）对晚期前列腺癌最初具有极好的抗癌效果，但大多数接受雄激素剥夺疗法治疗的前列腺癌最终会复发为去势抵抗性前列腺癌（castration-resistant prostate cancer，CRPC）。尽管异常激酶激活已被提议作为去势抵抗的机制，但 CRPC 的综合激酶谱仍不清楚。因此，我们旨在阐明 CRPC 的激酶组以及关键分子的作用。

方法

我们利用依赖雄激素的 LNCaP 和去势抵抗的 CxR 细胞中的激酶组阵列。通过定量聚合酶链反应和 Western blot 分析检查 Y 盒结合蛋白-1（Y-box binding protein-1，YB-1）对雄激素受体（androgen receptor，AR）表达的影响。通过 Cochran-Armitage 检验和 Cox 比例风险模型分别研究了通过基因分型确定的 YB-1 基因多态性与前列腺癌组织中 YB-1 表达的关联，以及转移性前列腺癌的结果。所有统计检验均为双侧检验。

结果

在 CRPC 细胞中，有 156 个激酶磷酸化位点（包括 ERK 和 RSK）被激活，导致 YB-1 的磷酸化增加，这是 CRPC 进展的关键分子。YB-1 信号调节 AR V7 的表达，YB-1 抑制增强了恩杂鲁胺的抗癌效果。此外，YB-1 基因中的多态性（rs12030724）影响了 93 例前列腺癌组织中的 YB-1 表达（YB-1 阳性率：TT 为 14.3%，AT 为 40.0%，AA 为 52.9%，P=.04），并与 104 例转移性前列腺癌病例患者的进展概率相关（AT/TT 与 AA，风险比=0.49，95%置信区间=0.32 至 0.77，P=.001）。