Upregulation of ATP Binding Cassette Subfamily C Member 5 facilitates Prostate Cancer progression and Enzalutamide resistance via the CDK1-mediated AR Ser81 Phosphorylation Pathway.
Upregulation of ATP Binding Cassette Subfamily C Member 5 facilitates Prostate Cancer progression and Enzalutamide resistance via the CDK1-mediated AR Ser81 Phosphorylation Pathway.
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ATP 结合盒亚家族 C 成员 5 的上调通过 CDK1 介导的 AR Ser81 磷酸化途径促进前列腺癌进展和恩杂鲁胺耐药性
DOI：
10.7150/ijbs.59559
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发表时间：
2021
影响因子：
9.2
通讯作者：
Zhou L
中科院分区：
文献类型：
--
作者：
Ji G;He S;Huang C;Gong Y;Li X;Zhou L
晚期前列腺癌，即去势抵抗性前列腺癌的治疗仍然颇具挑战。ATP结合盒转运蛋白超家族C成员5（ABCC5）在前列腺癌中的作用机制及其与耐药性的关系仍不明确。我们通过生物信息学方法以及在多个公共数据库和我们自己的前列腺癌队列中进行免疫组化分析，对ABCC5进行了表达和预后分析。通过体外和体内细胞增殖、迁移及侵袭实验，评估了ABCC5在前列腺癌细胞中的生物学功能。借助逆转录-定量聚合酶链反应（RT-qPCR）、蛋白质免疫印迹法和免疫荧光技术，确定了ABCC5对细胞周期蛋白依赖性激酶1（CDK1）的调控作用。ABCC5在前列腺癌中显著过表达，且与不良的临床病理特征和预后呈正相关。上调ABCC5可在体外和体内增强前列腺癌细胞的增殖、迁移和侵袭能力。从机制上讲，ABCC5通过与CDK1结合并抑制其蛋白降解发挥促肿瘤作用，这会促使CDK1使雄激素受体（AR）在丝氨酸81位点发生磷酸化，进而激活AR对靶基因的转录活性。此外，添加CDK1抑制剂或敲低CDK1可显著提高恩杂鲁胺对前列腺癌细胞的疗效。ABCC5 - CDK1 - AR调控通路有望成为晚期前列腺癌，尤其是去势抵抗性前列腺癌（CRPC）的潜在治疗靶点，以增强恩杂鲁胺的治疗效果。
The treatment of advanced prostate cancer, castration-resistant prostate cancer, remains challenging. The mechanisms of action of ATP binding cassette subfamily C member 5 (ABCC5) in prostate cancer and its relationship with drug resistance are still unclear. Expression and prognostic analyses of ABCC5 were performed through bioinformatic methods and immunohistochemistry analyses in multiple public databases as well as in our own prostate cancer cohort. The biological function of ABCC5 in prostate cancer cells was evaluated by in vitro and in vivo cell proliferation and migration and invasion assays. The regulation of CDK1 by ABCC5 was determined via RT-qPCR, western blots, and immunofluorescence. ABCC5 was significantly overexpressed in prostate cancer and positively associated with unfavorable clinicopathological features and prognosis. Upregulation of ABCC5 could enhance the cell proliferation, migration, and invasion of prostate cancer in vitro and in vivo. Mechanistically, ABCC5 exerts a protumor effect by binding to and inhibiting the protein degradation of CDK1, which promotes the phosphorylation of AR at Ser81 by CDK1 and activates the transcriptional activity of AR on target genes. Moreover, the addition of a CDK1 inhibitor or knockdown of CDK1 significantly improved the efficacy of enzalutamide on prostate cancer cells. The ABCC5-CDK1-AR regulatory pathway could be a potential therapeutic target for advanced prostate cancer, especially castration-resistant prostate cancer (CRPC), to enhance the therapeutic effect of enzalutamide.
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影响因子：
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