Quercetin induces protective autophagy and apoptosis through ER stress via the p-STAT3/Bcl-2 axis in ovarian cancer
Quercetin induces protective autophagy and apoptosis through ER stress via the p-STAT3/Bcl-2 axis in ovarian cancer
复制标题
槲皮素通过 p-STAT3/Bcl-2 轴在卵巢癌中通过 ER 应激诱导保护性自噬和细胞凋亡
DOI：
10.1007/s10495-016-1334-2
复制
发表时间：
2017-04-01
期刊：
影响因子：
7.2
通讯作者：
Gao, Q. L.
中科院分区：
文献类型：
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作者：
Liu, Y.;Gong, W.;Gao, Q. L.
槲皮素（3，3 '，4'，5，7-pentahydroxyflavone，Qu）是一种很有前途的癌症化学预防剂，因为它抑制疾病进展并促进细胞凋亡。在我们以前的研究中，我们证明了Qu可以引起ER应激，以增强卵巢癌（OC）的药物细胞毒性。然而，Qu诱导的ER应力在OC仍然知之甚少。在这里，我们证明了Qu通过p-STAT 3/Bcl-2轴在OC细胞系和原代OC细胞中诱导ER应激参与线粒体凋亡途径。出乎意料的是，ER应激的抑制没有逆转Qu诱导的细胞死亡。进一步的功能研究表明，Qu诱导的ER应激可以通过激活p-STAT 3/Bcl-2轴同时激活保护性自噬。此外，在卵巢癌小鼠异种移植模型中，自噬清除剂3-MA显示出增强Qu的抗癌作用。这些发现揭示了ER应激作为一把“双刃剑”参与Qu诱导的OC凋亡的新作用，并可能为生物修饰剂的临床研究提供一个新的角度，这些生物修饰剂可能通过靶向保护性自噬途径来规避患者的耐药性。
Quercetin (3,3',4',5,7-pentahydroxyflavone, Qu) is a promising cancer chemo-preventive agent for various cancers because it inhibits disease progression and promotes apoptotic cell death. In our previous study, we demonstrated that Qu could evoke ER stress to enhance drug cytotoxicity in ovarian cancer (OC). However, Qu-induced ER stress in OC is still poorly understood. Here, we demonstrated that Qu evoked ER stress to involve in mitochondria apoptosis pathway via the p-STAT3/Bcl-2 axis in OC cell lines and in primary OC cells. Unexpectedly, inhibition of ER stress did not reverse Qu-induced cell death. Further functional studies revealed that Qu-induced ER stress could activate protective autophagy concomitantly by activating the p-STAT3/Bcl-2 axis in this process. Moreover, the autophagy scavenger 3-MA was shown to enhance Qu's anticancer effects in an ovarian cancer mice xenograft model. These findings revealed a novel role of ER stress as a "double edge sword" participating in Qu-induced apoptosis of OC and might provide a new angle to consider in clinical studies of biological modifiers that may circumvent drug resistance in patients by targeting protective autophagy pathways.