Short hairpin RNA library-based functional screening identified ribosomal protein L31 that modulates prostate cancer cell growth via p53 pathway.
Short hairpin RNA library-based functional screening identified ribosomal protein L31 that modulates prostate cancer cell growth via p53 pathway.
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DOI：
10.1371/journal.pone.0108743
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Inoue S
中科院分区：
文献类型：
--
作者：
Maruyama Y;Miyazaki T;Ikeda K;Okumura T;Sato W;Horie-Inoue K;Okamoto K;Takeda S;Inoue S
雄激素受体是参与前列腺癌细胞增殖的主要转录因子。因此，使用抗雄激素（如比卡鲁胺）的激素疗法是该疾病的一线治疗。虽然激素治疗最初减少了肿瘤负担，但许多患者最终复发，发展成具有获得性内分泌抵抗的肿瘤。因此，阐明内分泌抵抗的分子机制是理解和开发晚期前列腺癌替代疗法的基本问题。在本研究中，我们进行了短发夹RNA（shRNA）介导的功能筛选，以确定参与比卡鲁胺介导的LNCaP前列腺癌细胞的影响的基因。在这些候选基因筛选使用火山图分析，核糖体蛋白L31（RPL31）被发现是必不可少的细胞增殖和细胞周期的进展比卡鲁胺耐药LNCaP（BicR）细胞，基于小干扰RNA（siRNA）介导的敲除实验。值得注意的是，RPL 31 mRNA在BicR细胞中比在亲本LNCaP细胞中更丰富地表达，并且来自ONCOMINE和The Cancer Genome Altas的临床数据显示，与良性前列腺组织相比，RPL 31在前列腺癌中过表达。有趣的是，在用RPL 31 siRNA处理的LNCaP和BicR细胞中，肿瘤抑制因子p53及其靶点p21和MDM2的蛋白水平增加。我们观察到RPL 31敲低后p53蛋白降解减少。此外，在RPL 31敲低后的生长和细胞周期的抑制用p53 siRNA处理部分恢复。这些结果表明RPL 31参与前列腺癌细胞的比卡鲁胺抗性生长。本研究中的shRNA介导的功能筛选为晚期前列腺癌的分子机制和治疗靶点提供了新的见解。
Androgen receptor is a primary transcription factor involved in the proliferation of prostate cancer cells. Thus, hormone therapy using antiandrogens, such as bicalutamide, is a first-line treatment for the disease. Although hormone therapy initially reduces the tumor burden, many patients eventually relapse, developing tumors with acquired endocrine resistance. Elucidation of the molecular mechanisms underlying endocrine resistance is therefore a fundamental issue for the understanding and development of alternative therapeutics for advanced prostate cancer. In the present study, we performed short hairpin RNA (shRNA)-mediated functional screening to identify genes involved in bicalutamide-mediated effects on LNCaP prostate cancer cells. Among such candidate genes selected by screening using volcano plot analysis, ribosomal protein L31 (RPL31) was found to be essential for cell proliferation and cell-cycle progression in bicalutamide-resistant LNCaP (BicR) cells, based on small interfering RNA (siRNA)-mediated knockdown experiments. Of note, RPL31 mRNA is more abundantly expressed in BicR cells than in parental LNCaP cells, and clinical data from ONCOMINE and The Cancer Genome Altas showed that RPL31 is overexpressed in prostate carcinomas compared with benign prostate tissues. Intriguingly, protein levels of the tumor suppressor p53 and its targets, p21 and MDM2, were increased in LNCaP and BicR cells treated with RPL31 siRNA. We observed decreased degradation of p53 protein after RPL31 knockdown. Moreover, the suppression of growth and cell cycle upon RPL31 knockdown was partially recovered with p53 siRNA treatment. These results suggest that RPL31 is involved in bicalutamide-resistant growth of prostate cancer cells. The shRNA-mediated functional screen in this study provides new insight into the molecular mechanisms and therapeutic targets of advanced prostate cancer.
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影响因子：
3.7
作者：
Lindstrom, Mikael S.;Nister, Monica
通讯作者：
Nister, Monica
影响因子：
9.7
作者：
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通讯作者：
Eisenberger, Mario A.
DOI：
10.1016/j.jsbmb.2005.04.029
发表时间：
2005-08-01
影响因子：
4.1
作者：
Hååg, P;Bektic, J;Eder, IE
通讯作者：
Eder, IE
核糖体蛋白 S26 调节 p53 活性以应对 DNA 损伤
影响因子：
8
作者：
Cui, D.;Li, L.;Tang, J.
通讯作者：
Tang, J.
影响因子：
5.3
作者：
Kang, H;Cui, KR;Zhao, KJ
通讯作者：
Zhao, KJ