Inhibition of ERα/ERK/P62 cascades induces "autophagic switch" in the estrogen receptor-positive breast cancer cells exposed to gemcitabine.
Inhibition of ERα/ERK/P62 cascades induces "autophagic switch" in the estrogen receptor-positive breast cancer cells exposed to gemcitabine.
复制标题
ER α/ERK/P62 级联的抑制可在暴露于吉西他滨的雌激素受体阳性乳腺癌细胞中诱导“自噬开关”
DOI：
10.18632/oncotarget.10363
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发表时间：
2016-07-26
期刊：
影响因子：
--
通讯作者：
Wang Q
中科院分区：
文献类型：
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作者：
Shen P;Chen M;He M;Chen L;Song Y;Xiao P;Wan X;Dai F;Pan T;Wang Q
多项临床研究表明，雌激素受体（ER）状态与乳腺恶性肿瘤对化疗的反应有关。自噬已成为肿瘤细胞应答抗癌治疗的重要细胞机制。本研究的目的是研究吉西他滨是否诱导自噬，更重要的是，这种自噬是否与吉西他滨在乳腺癌细胞中与ER状态相关的治疗效果功能相关。在我们的研究中，吉西他滨在ER+ MCF-7和ER− MDA-MB-231细胞中都显著诱导了自噬，而自噬在ER− MDA-MB-231细胞中起着不同的作用-细胞保护作用，在ER+ MCF-7细胞中起着细胞毒性作用。吉西他滨可激活MCF-7细胞的ERα-ERK-P62信号通路，增强自噬降解，导致自噬过度激活，最终导致不可逆的自噬性细胞死亡。小分子干扰RNA或PD 98059抑制MCF-7细胞中的ERα-ERK-P62级联反应，削弱自噬降解，并导致“自噬开关”-从细胞毒性自噬到细胞保护。此外，ER− BCap 37乳腺癌细胞系中ERα的稳定过表达增强了吉西他滨诱导的自噬通量，并将ER− BCap 37中的自噬细胞保护作用转换为ER+ BCap 37细胞中的细胞毒性作用。我们的研究首次证明ER状态通过调节乳腺癌细胞中的自噬来影响吉西他滨的疗效。
Several clinical trials revealed that estrogen receptor (ER) status had relevance to the response of mammary malignancy to chemotherapy. Autophagy has emerged as an important cellular mechanism of tumor cells in response to anticancer therapy. The aim of this study is to investigate whether gemcitabine induces autophagy, and more importantly, whether such autophagy is functional relevant to the therapeutic effects of gemcitabine in breast cancer cells in relation to the ER status. In our study, autophagy was induced both in ER+ MCF-7 and ER− MDA-MB-231 cells by gemcitabine markedly, while the autophagy plays distinct roles – cytoprotective in ER− MDA-MB-231 and cytotoxic in ER+ MCF-7 cells. Gemcitabine treatment leads to the activation of ERα-ERK-P62 signal pathway in MCF-7 cells which may augment the autophagic degradation, thus results in the excessive activation of autophagy and irreversible autophagic cell death eventually. Inhibition of ERα-ERK-P62 cascades in MCF-7 cells by small interfering RNA or PD98059 impairs the autophagic degradation, and leads to “autophagic switch” – from cytotoxic autophagy to cytoprotection. Moreover, stable overexpression of ERα in the ER− BCap37 breast cancer cell line enhances the gemcitabine-induced autophagy flux and switches the autophagic cytoprotection in ER− BCap37 to cytotoxicity effect in ER+ BCap37 cells. Our study firstly demonstrated that ER status influences gemcitabine efficacy via modulating the autophagy in breast cancer cells.