Downregulation of Human DAB2IP Gene Expression in Prostate Cancer Cells Results in Resistance to Ionizing Radiation
Downregulation of Human DAB2IP Gene Expression in Prostate Cancer Cells Results in Resistance to Ionizing Radiation
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DOI：
10.1158/0008-5472.can-09-2919
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发表时间：
2010-04-01
期刊：
影响因子：
11.2
通讯作者：
Saha, Debabrata
中科院分区：
文献类型：
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作者：
Kong, Zhaolu;Xie, Daxing;Saha, Debabrata
DAB2IP（DOC-2/DAB2 interactive protein，DOC-2/DAB2 interactive protein）是RAS-GTP酶激活蛋白家族的成员。它通常在转移性前列腺癌中下调，并已被报道为预测侵袭性前列腺癌风险的可能预后标志物。在这项研究中，我们提供了几条线的证据表明，转移性人前列腺癌PC3细胞缺乏DAB2IP（shDAB2IP）表现出增加的克隆生存响应电离辐射（IR）相比，对照细胞表达内源性水平的DAB2IP（shVector）。在DAB2IP缺陷的正常前列腺细胞中也观察到放射抗性。在DAB2IP缺陷的前列腺癌细胞中，这种增强的IR抗性主要是由于更快的DNA双链断裂（DSB）修复动力学。2戈伊照射后8 h，shDAB 2IP细胞的DSB修复率超过90%，而shVector细胞仅完成60%的DSB修复。第二，与对照细胞相比，照射后，DAB2IP缺陷细胞加强了一个强大的G（2）-M细胞周期检查点。最后，shDAB2IP细胞表现出抵抗IR诱导的细胞凋亡，这可能是由于促凋亡蛋白caspase-3、caspase-8和caspase-9的表达水平显著降低，而抗凋亡蛋白Bcl-2和STAT 3的表达水平显著高于shVector细胞。总之，由于增强的DSB修复、稳健的G（2）-M检查点控制和对IR诱导的细胞凋亡的抗性，DAB2IP在IR暴露后的前列腺细胞存活中起重要作用。因此，重要的是鉴定具有失调的DAB2 IP的患者，用于（a）评估前列腺癌风险和（B）替代治疗方案。Cancer Res; 70（7）; 2829 - 39. (C)2010年AACR。
DAB2IP (DOC-2/DAB2 interactive protein) is a member of the RAS-GTPase-activating protein family. It is often downregulated in metastatic prostate cancer and has been reported as a possible prognostic marker to predict the risk of aggressive prostate cancer. In this study, we furnish several lines of evidence indicating that metastatic human prostate cancer PC3 cells deficient in DAB2IP (shDAB2IP) exhibit increased clonogenic survival in response to ionizing radiation (IR) compared with control cells expressing an endogenous level of DAB2IP (shVector). Radioresistance was also observed in normal prostate cells that are deficient in DAB2IP. This enhanced resistance to IR in DAB2IP-deficient prostate cancer cells is primarily due to faster DNA double-strand break (DSB) repair kinetics. More than 90% of DSBs were repaired in shDAB2IP cells by 8 hours after 2 Gy radiation, whereas only 60% of DSB repair were completed in shVector cells at the same time. Second, upon irradiation, DAB2IP-deficient cells enforced a robust G(2)-M cell cycle checkpoint compared with control cells. Finally, shDAB2IP cells showed resistance to IR-induced apoptosis that could result from a striking decrease in the expression levels of proapoptotic proteins caspase-3, caspase-8, and caspase-9, and significantly higher levels of antiapoptotic proteins Bcl-2 and STAT3 than those in shVector cells. In summary, DAB2IP plays a significant role in prostate cell survival following IR exposure due to enhanced DSB repair, robust G(2)-M checkpoint control, and resistance to IR-induced apoptosis. Therefore, it is important to identify patients with dysregulated DAB2IP for (a) assessing prostate cancer risk and (b) alternative treatment regimens. Cancer Res; 70(7); 2829-39. (C) 2010 AACR.