Metformin suppresses proliferation and invasion of drug-resistant breast cancer cells by activation of the Hippo pathway
Metformin suppresses proliferation and invasion of drug-resistant breast cancer cells by activation of the Hippo pathway
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二甲双胍通过激活 Hippo 通路抑制耐药乳腺癌细胞的增殖和侵袭
DOI：
10.1111/jcmm.15241
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发表时间：
2020-04-12
影响因子：
5.3
通讯作者：
Liu, Peijun
中科院分区：
文献类型：
--
作者：
Liu, Jie;Li, Juan;Liu, Peijun
耐药性限制了乳腺癌治疗的临床疗效，并且在耐药性癌细胞中，Yes相关蛋白（雅普）的过表达或活化是常见的。因此，抑制雅普可降低对抗癌药物的抗性。二甲双胍（MET）是一种一线糖尿病药物，也具有抗肿瘤活性，可诱导AMP活化蛋白激酶（AMPK），直接磷酸化雅普并抑制雅普转录活性。在这项研究中，我们确定MET对耐药乳腺癌细胞增殖和侵袭的影响，然后研究潜在的分子机制。我们的体内和体外实验表明，MET通过AMPK非依赖性途径减少雅普核定位来抑制乳腺癌。在药物敏感细胞中，MET通过增加KIBRA和FRMD6表达激活Hippo通路，但这在耐药细胞中没有发生。Scribble（SCRIB）是一种细胞极性蛋白，相对于敏感细胞，在他莫昔芬和紫杉醇耐药乳腺癌细胞中显著下调。我们还发现MET通过增加SCRIB的表达和细胞膜定位来抑制耐药乳腺癌细胞的增殖和侵袭，这增强了SCRIB与MST 1和LATS 1的相互作用，并抑制了雅普的核定位和转录活性。
Drug resistance limits the clinical efficacy of breast cancer therapies, and overexpression or activation of Yes-associated protein (YAP) is common in drug-resistant cancer cells. Thus, inhibition of YAP may reduce resistance to anti-cancer drugs. Metformin (MET), a first-line diabetes medication that also has anti-tumour activities, induces AMP-activated protein kinase (AMPK), directly phosphorylates YAP and inhibits YAP transcriptional activity. In this study, we determined the effect of MET on the proliferation and invasion of drug-resistant breast cancer cells and then investigated the underlying molecular mechanism. Our in vivo and in vitro experiments indicated that MET suppressed breast cancer by an AMPK-independent pathway to decrease YAP nuclear localization. In drug-sensitive cells, MET activated the Hippo pathway by increasing KIBRA and FRMD6 expression, but this did not occur in drug-resistant cells. Scribble (SCRIB), a cell polarity protein, was notably down-regulated in tamoxifen- and paclitaxel-resistant breast cancer cells relative to sensitive cells. We also found that MET suppressed the proliferation and invasion of drug-resistant breast cancer cells by increasing the expression and cell membrane localization of SCRIB, which enhanced the interaction of SCRIB with MST1 and LATS1, and inhibited YAP nuclear localization and transcriptional activity.