Metformin inhibits estrogen-dependent endometrial cancer cell growth by activating the AMPK-FOXO1 signal pathway.
Metformin inhibits estrogen-dependent endometrial cancer cell growth by activating the AMPK-FOXO1 signal pathway.
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二甲双胍通过激活 AMPK-FOXO1 信号通路抑制雌激素依赖性子宫内膜癌细胞生长。
DOI：
10.1111/cas.13083
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发表时间：
2016-12
期刊：
影响因子：
5.7
通讯作者：
Cheng J
中科院分区：
文献类型：
--
作者：
Zou J;Hong L;Luo C;Li Z;Zhu Y;Huang T;Zhang Y;Yuan H;Hu Y;Wen T;Zhuang W;Cai B;Zhang X;Huang J;Cheng J
二甲双胍是一种常用于治疗II型糖尿病的口服双胍，最近报道其具有抗增殖特性，可用于预防和治疗多种癌症。这种影响的机制尚未完全阐明。我们的研究显示，与正常对照子宫内膜相比，雌激素依赖性子宫内膜癌（EC）肿瘤中AMP活化蛋白激酶（AMPK）磷酸化和核人Forkhead box O 1（FOXO 1）蛋白显著丢失。在体外，二甲双胍处理以时间依赖性方式抑制EC细胞生长;这种作用通过与AMPK抑制剂化合物C共处理而被抵消。在石川和HEC-1B细胞中，二甲双胍降低FOXO 1磷酸化并增加FOXO 1核定位，FOXO 1 mRNA表达无显著增加。此外，化合物C阻断了二甲双胍诱导的FOXO 1及其磷酸化蛋白的变化，表明二甲双胍通过AMPK活化上调FOXO 1活性。用胰岛素治疗后获得了类似的结果。此外，用FOXO 1的siRNA转染取消了二甲双胍抑制的细胞生长，表明FOXO 1介导二甲双胍抑制EC细胞增殖。异种移植小鼠模型进一步显示，二甲双胍抑制HEC-1B肿瘤生长，同时下调ki-67，上调AMPK磷酸化和核FOXO 1蛋白。综上所述，这些数据提供了二甲双胍通过调节FOXO 1发挥抗抑郁作用的新机制，并表明AMPK-FOXO 1通路可能是开发新抗抑郁药物的治疗靶点。
Metformin is an oral biguanide commonly used for treating type II diabetes and has recently been reported to possess antiproliferative properties that can be exploited for the prevention and treatment of a variety of cancers. The mechanisms underlying this effect have not been fully elucidated. Our study shows a marked loss of AMP‐activated protein kinase (AMPK) phosphorylation and nuclear human Forkhead box O1 (FOXO1) protein in estrogen‐dependent endometrial cancer (EC) tumors compared to normal control endometrium. Metformin treatment suppressed EC cell growth in a time‐dependent manner in vitro; this effect was cancelled by cotreatment with an AMPK inhibitor, compound C. Metformin decreased FOXO1 phosphorylation and increased FOXO1 nuclear localization in Ishikawa and HEC‐1B cells, with non‐significant increase in FOXO1 mRNA expression. Moreover, compound C blocked the metformin‐induced changes of FOXO1 and its phosphorylation protein, suggesting that metformin upregulated FOXO1 activity by AMPK activation. Similar results were obtained after treatment with insulin. In addition, transfection with siRNA for FOXO1 cancelled metformin‐inhibited cell growth, indicating that FOXO1 mediated metformin to inhibit EC cell proliferation. A xenograft mouse model further revealed that metformin suppressed HEC‐1B tumor growth, accompanied by downregulated ki‐67 and upregulated AMPK phosphorylation and nuclear FOXO1 protein. Taken together, these data provide a novel mechanism of antineoplastic effect for metformin through the regulation of FOXO1, and suggest that the AMPK–FOXO1 pathway may be a therapeutic target to the development of new antineoplastic drugs.
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影响因子：
7.3
作者：
Arunachalam G;Samuel SM;Marei I;Ding H;Triggle CR
通讯作者：
Triggle CR
影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
5.2
作者：
Greer EL;Banko MR;Brunet A
通讯作者：
Brunet A
影响因子：
45.3
作者：
Jiralerspong, Sao;Palla, Shana L.;Gonzalez-Angulo, Ana M.
通讯作者：
Gonzalez-Angulo, Ana M.
影响因子：
4
作者：
Huang, Haojie;Tindall, Donald J.
通讯作者：
Tindall, Donald J.