Metformin is a potent inhibitor of endometrial cancer cell proliferation--implications for a novel treatment strategy.
Metformin is a potent inhibitor of endometrial cancer cell proliferation--implications for a novel treatment strategy.
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DOI：
10.1016/j.ygyno.2009.09.024
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发表时间：
2010-01
影响因子：
4.7
通讯作者：
Bae-Jump VL
中科院分区：
文献类型：
--
作者：
Cantrell LA;Zhou C;Mendivil A;Malloy KM;Gehrig PA;Bae-Jump VL
肥胖和糖尿病是驱动I型子宫内膜癌发展的强大危险因素。最近的流行病学证据表明，二甲双胍可以降低糖尿病患者的癌症风险和癌症死亡率。为了更好地了解二甲双胍的抗肿瘤潜能，我们的目标是评估二甲双胍对子宫内膜癌细胞系二甲双胍细胞信号传导关键靶点增殖和表达的影响。使用子宫内膜癌细胞系ECC-1和Ishikawa。暴露于二甲双胍后评估细胞增殖。流式细胞术观察细胞周期进展。ELISA检测caspase-3活性。实时RT-PCR检测hTERT表达。Western免疫印迹法检测二甲双胍下游靶点的表达。二甲双胍在两种细胞系中均以剂量依赖性的方式抑制生长（IC50为1 mM）。二甲双胍治疗导致G1停止，诱导细胞凋亡，降低hTERT表达。Western免疫印迹分析表明，二甲双胍在暴露24小时内诱导其直接下游介质AMPK磷酸化。与此同时，二甲双胍治疗降低了S6蛋白的磷酸化，S6蛋白是mTOR通路的一个关键靶点。我们发现二甲双胍是子宫内膜癌细胞系细胞增殖的有效抑制剂。这种作用部分通过AMPK激活和随后的mTOR通路抑制介导。本研究为今后二甲双胍作为子宫内膜癌防治策略的研究提供了科学依据。
Obesity and diabetes are strong risk factors that drive the development of type I endometrial cancers. Recent epidemiological evidence suggests that metformin may lower cancer risk and reduce rates of cancer deaths among diabetic patients. In order to better understand metformin's anti-tumorigenic potential, our goal was to assess the effect of metformin on proliferation and expression of key targets of metformin cell signaling in endometrial cancer cell lines. The endometrial cancer cell lines, ECC-1 and Ishikawa, were used. Cell proliferation was assessed after exposure to metformin. Cell cycle progression was evaluated by flow cytometry. Apoptosis was assessed by ELISA for caspase-3 activity. hTERT expression was determined by real-time RT-PCR. Western immunoblotting was performed to determine the expression of the downstream targets of metformin. Metformin potently inhibited growth in a dose-dependent manner in both cell lines (IC50 of 1 mM). Treatment with metformin resulted in G1 arrest, induction of apoptosis and decreased hTERT expression. Western immunoblot analysis demonstrated that metformin induced phosphorylation of AMPK, its immediate downstream mediator, within 24 hours of exposure. In parallel, treatment with metformin decreased phosphorylation of S6 protein, a key target of the mTOR pathway. We find that metformin is a potent inhibitor of cell proliferation in endometrial cancer cell lines. This effect is partially mediated through AMPK activation and subsequent inhibition of the mTOR pathway. This work should provide the scientific foundation for future investigation of metformin as a strategy for endometrial cancer prevention and treatment.
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影响因子：
4.7
作者：
Gotlieb, Walter H.;Saumet, Julio;Bruchim, Ilan
通讯作者：
Bruchim, Ilan
影响因子：
13.6
作者：
Carling, David
通讯作者：
Carling, David
影响因子：
56.9
作者：
Shaw, RJ;Lamia, KA;Cantley, LC
通讯作者：
Cantley, LC
DOI：
10.1073/pnas.171060098
发表时间：
2001-08-28
影响因子：
11.1
作者：
Podsypanina, K;Lee, RT;Parsons, R
通讯作者：
Parsons, R
影响因子：
11.2
作者：
Contreras, Cristina M.;Gurumurthy, Sushma;Castrillon, Diego H.
通讯作者：
Castrillon, Diego H.