Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells
Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells
复制标题
极光激酶 A 抑制诱导的自噬引发乳腺癌细胞耐药性
DOI：
10.4161/auto.22110
复制
发表时间：
2012-12-01
期刊：
影响因子：
13.3
通讯作者：
Liu, Quentin
中科院分区：
文献类型：
--
作者：
Zou, Zhengzhi;Yuan, Zhongyu;Liu, Quentin
我们以前已经表明，有丝分裂激酶极光激酶A（AURKA）在癌细胞中的表达升高，促进转移表型的发展，并在临床上与不良预后相关。在这里，我们首次揭示了AURKA和自噬相关蛋白SQSTM 1在乳腺癌中的临床正相关性，并进一步证明了AURKA通过自噬调节SQSTM 1。事实上，通过siRNA消耗或通过小分子VX-680化学抑制AURKA增加了微管相关蛋白1轻链3-II（LC 3-II）的水平和自噬体的数量，沿着SQSTM 1的减少。相反，AURKA的过表达抑制自噬，如通过在营养剥夺或正常条件下降低LC 3-II和增加SQSTM 1所评估的。此外，磷酸化形式的RPS 6 KB 1和雷帕霉素的机制目标（MTOR）的AURKA的过表达升高，而它们被抑制的AURKA的消耗或抑制。此外，通过MTOR复合物1/2的抑制剂PP 242抑制MTOR，消除了AURKA过表达的BT-549细胞中LC 3-II和SQSTM 1的变化，表明AURKA抑制的自噬可能与MTOR激活相关。最后，通过耗尽LC 3或ATG 5抑制自噬，使乳腺癌细胞对VX-680诱导的凋亡敏感。在用自噬抑制剂氯喹（CQ）和巴弗洛霉素A1（BAF）处理的细胞中观察到类似的发现。因此，我们的数据揭示了AURKA作为自噬的负调节剂的新作用，表明AURKA抑制诱导自噬，这可能代表了乳腺癌靶向治疗中耐药的新机制。
We have previously shown that elevated expression of mitotic kinase aurora kinase A (AURKA) in cancer cells promotes the development of metastatic phenotypes and is associated clinically with adverse prognosis. Here, we first revealed a clinically positive correlation between AURKA and autophagy-associated protein SQSTM1 in breast cancer and further demonstrated that AURKA regulated SQSTM1 through autophagy. Indeed, depletion by siRNA or chemical inhibition of AURKA by the small molecule VX-680 increased both the level of microtubule-associated protein 1 light chain 3-II (LC3-II) and the number of autophagosomes, along with decreased SQSTM1. Conversely, overexpression of AURKA inhibited autophagy, as assessed by decreased LC3-II and increased SQSTM1 either upon nutrient deprivation or normal conditions. In addition, phosphorylated forms of both RPS6KB1 and mechanistic target of rapamycin (MTOR) were elevated by overexpression of AURKA whereas they were suppressed by depletion or inhibition of AURKA. Moreover, inhibition of MTOR by PP242, an inhibitor of MTOR complex1/2, abrogated the changes in both LC3-II and SQSTM1 in AURKA-overexpressing BT-549 cells, suggesting that AURKA-suppressed autophagy might be associated with MTOR activation. Lastly, repression of autophagy by depletion of either LC3 or ATG5, sensitized breast cancer cells to VX-680-induced apoptosis. Similar findings were observed in cells treated with the autophagy inhibitors chloroquine (CQ) and bafilomycin A1 (BAF). Our data thus revealed a novel role of AURKA as a negative regulator of autophagy, showing that AURKA inhibition induced autophagy, which may represent a novel mechanism of drug resistance in apoptosis-aimed therapy for breast cancer.