Silencing of MicroRNA-21 confers the sensitivity to tamoxifen and fulvestrant by enhancing autophagic cell death through inhibition of the PI3K-AKT-mTOR pathway in breast cancer cells
Silencing of MicroRNA-21 confers the sensitivity to tamoxifen and fulvestrant by enhancing autophagic cell death through inhibition of the PI3K-AKT-mTOR pathway in breast cancer cells
复制标题
MicroRNA-21 的沉默通过抑制乳腺癌细胞中的 PI3K-AKT-mTOR 通路来增强自噬性细胞死亡，从而赋予他莫昔芬和氟维司群敏感性
DOI：
10.1016/j.biopha.2015.11.005
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发表时间：
2016-02-01
影响因子：
7.5
通讯作者：
Qu, Xianjun
中科院分区：
文献类型：
--
作者：
Yu, Xinfeng;Li, Ruilian;Qu, Xianjun
他莫昔芬（TAM）和氟维司汀（FUL）是雌激素受体- α阳性（ER+）乳腺癌患者的主要辅助治疗。然而，内分泌对TAM和FUL的抵抗是成功治疗的一大障碍。我们假设miR-21可能通过调节细胞自噬来改变乳腺癌细胞对TAM或FUL的敏感性。使用ER+乳腺癌细胞，我们敲低miR-21。转染miR-21抑制剂，然后将细胞暴露于TAM或FUL，测定细胞凋亡和自噬的百分比。miR-21敲低可显著增加TAM或full诱导的ER+乳腺癌细胞凋亡。此外，MCF-7细胞中miR-21的沉默增强了基础水平和TAM或full诱导水平的细胞自噬。在mir -21敲低的MCF-7细胞中，自噬的增加也通过beclin-1、LC3-II和GFP-LC3点的增加来表明。重要的是，miR-21的敲低有助于自噬细胞死亡，这是TAM诱导的miR-21抑制剂转染细胞死亡的部分原因。进一步分析表明，miR-21抑制剂通过抑制PI3K-AKT-mTOR通路促进自噬细胞死亡。MiR-21通过抑制PI3K-AKT-mTOR通路，靶向磷酸酶和紧张素同源物（PTEN），协调自噬和凋亡的功能。综上所述，miR-21的沉默通过增加自噬细胞死亡增加了ER+乳腺癌细胞对TAM或FUL的敏感性。靶向自噬相关的mirna是克服内分泌对TAM和FUL的抗性的潜在策略。(C) 2015 Elsevier Masson SAS。版权所有。
Tamoxifen (TAM) and fulvestrant (FUL) represent the major adjuvant therapy to estrogen receptor-alpha positive (ER+) breast cancer patients. However, endocrine resistance to TAM and FUL is a great impediment for successful treatment. We hypothesized that miR-21 might alter the sensitivity of breast cancer cells to TAM or FUL by regulating cell autophagy. Using the ER+ breast cancer cells, we knockdown miR-21. by transfection with miR-21 inhibitor, then the cells were exposed to TAM or FUL and the percentages of apoptosis and autophagy were determined. Knockdown of miR-21 significantly increased the TAM or FUL-induced apoptosis in ER+ breast cancer cells. Further, silencing of miR-21 in MCF-7 cells enhanced cell autophagy at both basal and TAM or FUL-induced level. The increase of autophagy in miR-21-knockdown MCF-7 cells was also indicated by increase of beclin-1, LC3-II and increased GFP-LC3 dots. Importantly, knockdown of miR-21 contributed to autophagic cell death, which is responsible for part of TAM induced cell death in miR-21 inhibitor-transfected cells. Further analysis suggested that miR-21 inhibitor enhance autophagic cell death through inhibition of PI3K-AKT-mTOR pathway. MiR-21 coordinated the function of autophagy and apoptosis by targeting Phosphatase and tensin homolog (PTEN) through inhibition of PI3K-AKT-mTOR pathway. In conclusion, silencing of miR-21 increased the sensitivity of ER+ breast cancer cells to TAM or FUL by increasing autophagic cell death. Targeting autophagy-related miRNAs is a potential strategy for overcoming endocrine resistance to TAM and FUL. (C) 2015 Elsevier Masson SAS. All rights reserved.