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肾癌细胞中Nek1表达增加与对DNA损伤治疗的敏感性降低有关。

Increased Nek1 expression in renal cell carcinoma cells is associated with decreased sensitivity to DNA-damaging treatment.

作者信息

Chen Yumay, Chen Chi-Fen, Polci Rosaria, Wei Randy, Riley Daniel J, Chen Phang-Lang

机构信息

Department of Medicine, Division of Endocrinology, University of California at Irvine.

Department of Biological Chemistry, University of California at Irvine.

出版信息

Oncotarget. 2014 Jun 30;5(12):4283-94. doi: 10.18632/oncotarget.2005.

DOI:10.18632/oncotarget.2005
PMID:24970796
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4147323/
Abstract

Renal cell carcinoma (RCC) is a heterogeneous disease with resistance to systemic chemotherapy. Elevated expression of multiple drug resistance (MDR) has been suggested to be one of the mechanisms for this resistance. Here, we provide an alternative mechanism to explain RCC's resistance to chemotherapy-induced apoptosis. Never-in mitosis A-related protein kinase 1 (Nek1) plays an important role in DNA damage response and proper checkpoint activation. The association of Nek1 with the voltage-dependent anion channel (VDAC1) is a critical determinant of cell survival following DNA-damaging treatment. We report here that Nek1 is highly expressed in RCC tumor and cultured RCC cells compared to that of normal renal tubular epithelial cells (RTE). The association between Nek1 and VDAC1 is genotoxic dependent: prolonged Nek1/VDAC1 dissociation will lead to VDAC1 dephosphorylation and initiate apoptosis. Down-regulation of Nek1 expression in RCC cells enhanced their sensitivity to DNA-damaging treatment. Collectively, these results suggest that the increased Nek1 expression in RCC cells maintain persistent VDAC1 phosphorylation, closing its channel and preventing the onset of apoptosis under genotoxic insults. Based on these results, we believe that Nek1 can serve as a potential therapeutic target for drug development in the treatment of RCC.

摘要

肾细胞癌（RCC）是一种对全身化疗具有抗性的异质性疾病。多药耐药性（MDR）表达升高被认为是这种抗性的机制之一。在此，我们提供了一种替代机制来解释RCC对化疗诱导的细胞凋亡的抗性。从未有丝分裂A相关蛋白激酶1（Nek1）在DNA损伤反应和适当的检查点激活中起重要作用。Nek1与电压依赖性阴离子通道（VDAC1）的关联是DNA损伤处理后细胞存活的关键决定因素。我们在此报告，与正常肾小管上皮细胞（RTE）相比，Nek1在RCC肿瘤和培养的RCC细胞中高度表达。Nek1与VDAC1之间的关联是基因毒性依赖性的：Nek1/VDAC1的长时间解离将导致VDAC1去磷酸化并引发细胞凋亡。RCC细胞中Nek1表达的下调增强了它们对DNA损伤处理的敏感性。总体而言，这些结果表明，RCC细胞中Nek1表达的增加维持了VDAC1的持续磷酸化，关闭其通道并在基因毒性损伤下阻止细胞凋亡的发生。基于这些结果，我们认为Nek1可作为RCC治疗中药物开发的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfc2/4147323/ea19b3b4e0a9/oncotarget-05-4283-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfc2/4147323/70c148fffa4c/oncotarget-05-4283-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfc2/4147323/a6f6dfcb2bff/oncotarget-05-4283-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfc2/4147323/0761e24e456c/oncotarget-05-4283-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfc2/4147323/5dc158639748/oncotarget-05-4283-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfc2/4147323/ea19b3b4e0a9/oncotarget-05-4283-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfc2/4147323/70c148fffa4c/oncotarget-05-4283-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfc2/4147323/a6f6dfcb2bff/oncotarget-05-4283-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfc2/4147323/0761e24e456c/oncotarget-05-4283-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfc2/4147323/5dc158639748/oncotarget-05-4283-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfc2/4147323/ea19b3b4e0a9/oncotarget-05-4283-g005.jpg

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