Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling.
Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling.
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二甲双胍通过下调 Stat3 信号促进食管鳞状细胞癌自噬和凋亡
DOI：
10.1038/cddis.2014.59
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发表时间：
2014-02-27
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
抗糖尿病药物二甲双胍在许多类型的恶性肿瘤中具有化学预防和抗肿瘤作用。然而，导致二甲双胍作用的机制似乎不同，而且在不同类型的癌症中可能有所不同。了解不同癌症特有的分子和细胞机制对于优化二甲双胍治疗不同癌症类型的策略非常重要。在此，我们研究了二甲双胍对食管鳞状细胞癌(ESCC)细胞的体外和体内作用。二甲双胍选择性地抑制ESCC肿瘤细胞的生长，但不抑制永生化的非癌食道上皮细胞。除细胞凋亡外，二甲双胍还触发了自噬。药物或遗传抑制自噬敏化的ESCC细胞对二甲双胍诱导的细胞凋亡的抑制。机制上，信号转导和转录激活子3(STAT3)及其下游靶点Bcl2被二甲双胍灭活。因此，小干扰RNA(SiRNA)介导的STAT3基因敲除增强了二甲双胍诱导的自噬和细胞凋亡，同时也增强了二甲双胍对细胞活力的抑制作用。同样，抑制细胞凋亡和自噬的原癌基因Bcl2也被二甲双胍抑制。异位表达Bcl2对二甲双胍诱导的细胞自噬和凋亡的保护作用在体内，二甲双胍下调STAT3活性和Bcl2表达，诱导细胞凋亡和自噬，抑制肿瘤生长。总之，STAT3-Bcl2通路的失活通过促进细胞凋亡和自噬之间的串扰，参与了二甲双胍抑制ESCC的生长。
The antidiabetic drug metformin exerts chemopreventive and antineoplastic effects in many types of malignancies. However, the mechanisms responsible for metformin actions appear diverse and may differ in different types of cancer. Understanding the molecular and cellular mechanisms specific for different cancers is important to optimize strategy for metformin treatment in different cancer types. Here, we investigate the in vitro and in vivo effects of metformin on esophageal squamous cell carcinoma (ESCC) cells. Metformin selectively inhibited cell growth in ESCC tumor cells but not immortalized noncancerous esophageal epithelial cells. In addition to apoptosis, metformin triggered autophagy. Pharmacological or genetic inhibition of autophagy sensitized ESCC cells to metformin-induced apoptotic cell death. Mechanistically, signal transducer and activator of transcription 3 (Stat3) and its downstream target Bcl-2 was inactivated by metformin treatment. Accordingly, small interfering RNA (siRNA)-mediated Stat3 knockdown enhanced metformin-induced autophagy and apoptosis, and concomitantly enhanced the inhibitory effect of metformin on cell viability. Similarly, the Bcl-2 proto-oncogene, an inhibitor of both apoptosis and autophagy, was repressed by metformin. Ectopic expression of Bcl-2 protected cells from metformin-mediated autophagy and apoptosis. In vivo, metformin downregulated Stat3 activity and Bcl-2 expression, induced apoptosis and autophagy, and inhibited tumor growth. Together, inactivation of Stat3-Bcl-2 pathway contributes to metformin-induced growth inhibition of ESCC by facilitating crosstalk between apoptosis and autophagy.
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影响因子：
13.3
作者：
Akar, Ugur;Chaves-Reyez, Arturo;Ozpolat, Bulent
通讯作者：
Ozpolat, Bulent
影响因子：
3.5
作者：
Marino, Guillermo;Ugalde, Alejandro P.;Lopez-Otin, Carlos
通讯作者：
Lopez-Otin, Carlos
影响因子：
11.2
作者：
Buzzai, Monica;Jones, Russell G.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
4.3
作者：
Deng, Xin-Sheng;Wang, Shuiliang;Thor, Ann D.
通讯作者：
Thor, Ann D.
影响因子：
11.4
作者：
Nielsen, M;Kæstel, CG;Odum, N
通讯作者：
Odum, N