Metformin inhibits skin tumor promotion in overweight and obese mice.
Metformin inhibits skin tumor promotion in overweight and obese mice.
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DOI：
10.1158/1940-6207.capr-13-0110
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发表时间：
2014-01
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影响因子：
--
通讯作者：
DiGiovanni J
中科院分区：
文献类型：
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作者：
Checkley LA;Rho O;Angel JM;Cho J;Blando J;Beltran L;Hursting SD;DiGiovanni J
在本研究中，在维持超重对照饮食或肥胖诱导饮食的小鼠中分析二甲双胍抑制12-O-十四酰基佛波醇-13-乙酸酯（TPA）促进皮肤肿瘤的能力。包括雷帕霉素用于比较，并且还评估了二甲双胍和雷帕霉素的组合。二甲双胍（在饮用水中给药）和雷帕霉素（局部给药）以剂量依赖性方式抑制超重和肥胖小鼠乳头状瘤和鳞状细胞癌的发生。这两种化合物的低剂量组合显示出对肿瘤发展的相加抑制作用。二甲双胍治疗还可以缩小乳头状瘤的大小。有趣的是，所有治疗似乎至少对抑制肥胖小鼠中的肿瘤形成同样有效，并且与超重对照小鼠相比，二甲双胍和雷帕霉素在减少肥胖小鼠中的肿瘤大小方面更有效。二甲双胍对皮肤肿瘤发展的影响与TPA诱导的表皮过度增殖显著减少相关。此外，二甲双胍治疗导致表皮AMPK活化，并通过mTORC 1和p70 S6 K减弱信号传导。二甲双胍和雷帕霉素的组合在阻断TPA诱导的表皮mTORC 1信号传导方面更有效，这与对皮肤肿瘤促进的更大抑制作用一致。总的来说，目前的数据表明，二甲双胍在饮用水中给药可有效抑制超重和肥胖小鼠的皮肤肿瘤促进作用，其机制涉及表皮AMPK的激活和mTORC 1下游信号转导的减弱。
In the present study, the ability of metformin to inhibit skin tumor promotion by 12-O- tetradecanoylphorbol-13-acetate (TPA) was analyzed in mice maintained on either an overweight control diet or an obesity inducing diet. Rapamycin was included for comparison, and a combination of metformin and rapamycin was also evaluated. Metformin (given in the drinking water) and rapamycin (given topically) inhibited development of both papillomas and squamous cell carcinomas in overweight and obese mice in a dose-dependent manner. A low dose combination of these two compounds displayed an additive inhibitory effect on tumor development. Metformin treatment also reduced the size of papillomas. Interestingly, all treatments appeared to be at least as effective for inhibiting tumor formation in obese mice and both metformin and rapamycin were more effective at reducing tumor size in obese mice compared to overweight control mice. The effect of metformin on skin tumor development was associated with a significant reduction in TPA-induced epidermal hyperproliferation. Furthermore, treatment with metformin led to activation of epidermal AMPK and attenuated signaling through mTORC1 and p70S6K. Combinations of metformin and rapamycin were more effective at blocking epidermal mTORC1 signaling induced by TPA consistent with the greater inhibitory effect on skin tumor promotion. Collectively, the current data demonstrate that metformin given in the drinking water effectively inhibited skin tumor promotion in both overweight and obese mice and that the mechanism involves activation of epidermal AMPK and attenuated signaling downstream of mTORC1.