Suppression of autophagy by FIP200 deletion impairs DNA damage repair and increases cell death upon treatments with anticancer agents.
Suppression of autophagy by FIP200 deletion impairs DNA damage repair and increases cell death upon treatments with anticancer agents.
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DOI：
10.1158/1541-7786.mcr-11-0098
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发表时间：
2011-09
期刊：
影响因子：
--
通讯作者：
Guan JL
中科院分区：
文献类型：
--
作者：
Bae H;Guan JL
自噬是溶酶体对细胞内蛋白质和细胞器的整体降解过程。最近的研究表明，FIP200 （200 kDa fak家族相互作用蛋白）是哺乳动物自噬的重要组成部分，与乳腺癌有关。本研究表明，在小鼠胚胎成纤维细胞（mef）中，FIP200的失活导致电离辐射和抗癌药物诱导的DNA损伤修复缺陷。在接受喜树碱（一种拓扑异构酶I抑制剂和化疗药物）治疗后，持续的DNA损伤与FIP200敲除（KO） MEFs的凋亡增加和生存率降低相关。在FIP200 KO MEFs中重新表达FIP200可以有效修复DNA损伤和细胞存活。此外，敲除FIP200 KO MEFs中p62表达的增加可以挽救受损的DNA损伤修复和cpt诱导的细胞死亡。相反，用n -乙酰半胱氨酸处理细胞不会影响FIP200 KO mef中的这些缺陷。最后，FIP200 KO MEFs也表现出DNA损伤修复缺陷，与对照MEFs相比，当使用依托泊苷（一种拓扑异构酶II抑制剂和另一种抗癌剂）处理时，细胞死亡增加。综上所述，这些结果确定了FIP200通过其自噬活性调控DNA损伤反应和细胞存活的新功能，并提示FIP200或其他自噬蛋白可能作为治疗的潜在靶点，以提高使用DNA损伤诱导剂治疗癌症的效率。
Autophagy is a lysosomal bulk degradation process for intracellular protein and organelles. FIP200 (200 kDa FAK-family interacting protein) is an essential component of mammalian autophagy that is implicated in breast cancer in recent studies. Here we show that inactivation of FIP200 resulted in deficient repair of DNA damage induced by ionizing radiation and anticancer agents in mouse embryonic fibroblasts (MEFs). The persistent DNA damage correlated to increased apoptosis and reduced survival of FIP200 knockout (KO) MEFs after treatments with camptothecin (CPT), a topoisomerase I inhibitor and chemotherapeutic agent. Re-expression of FIP200 in FIP200 KO MEFs restored both efficient DNA damage repair and cell survival. Furthermore, knock-down of the increased p62 expression in FIP200 KO MEFs rescued the impaired DNA damage repair and CPT-induced cell death. In contrast, treatment of cells with N-acetyl-cysteine did not affect these defects in FIP200 KO MEFs. Lastly, FIP200 KO MEFs also showed deficient DNA damage repair and increased cell death compared to control MEFs, when treated with etoposide, a topoisomerase II inhibitor and another anticancer agent. Together, these results identify a new function for FIP200 in the regulation of DNA damage response and cell survival through its activity in autophagy, and suggest the possibility of FIP200 or other autophagy proteins as a potential target for treatment to enhance the efficiency of cancer therapy using DNA damage-inducing agents.