Metformin, an antidiabetic agent reduces growth of cutaneous squamous cell carcinoma by targeting mTOR signaling pathway.
Metformin, an antidiabetic agent reduces growth of cutaneous squamous cell carcinoma by targeting mTOR signaling pathway.
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DOI：
10.1111/j.1751-1097.2012.01165.x
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发表时间：
2012-09
影响因子：
3.3
通讯作者：
Athar M
中科院分区：
文献类型：
--
作者：
Chaudhary SC;Kurundkar D;Elmets CA;Kopelovich L;Athar M
双胍二甲双胍广泛用于治疗II型糖尿病。其在多种肿瘤细胞中的抗增殖和促凋亡作用表明其具有潜在的癌症化学预防候选资格。我们在此报告二甲双胍显著抑制nu/nu小鼠中人表皮样A431肿瘤异种移植物的生长，这与增殖生物标志物PCNA和细胞周期蛋白D1/B1的显著减少有关。这种肿瘤生长减少伴随着增强的凋亡性细胞死亡和Bax：Bcl 2比率的增加。二甲双胍显示抗肿瘤作用的机制似乎依赖于抑制核因子κ B（NFk B）和mTOR信号通路。NFkB抑制蛋白IKBα磷酸化水平降低，同时NFkB转录靶蛋白iNOS/考克斯-2的表达水平降低。此外，ERK/p38驱动的MAP激酶信号转导的激活减少。类似地，通过Ser 473处磷酸化的减少以及伴随的mTOR信号传导途径的减少来评估的AKT信号传导激活也被注意到，因为mTOR调节蛋白p70 S6 K和4 E-BP-1的磷酸化显著减少。同样，还观察到由AKT激酶进行的GSK 3 β磷酸化降低。这些结果表明，二甲双胍通过抑制NFkB和mTOR信号通路阻断SCC生长。
The biguanide metformin is widely used for the treatment of type II diabetes. Its anti-proliferative and pro-apoptotic effects in various tumor cells suggest its potential candidacy for cancer chemoprevention. Here we report that metformin significantly inhibited human epidermoid A431 tumor xenograft growth in nu/nu mice, which was associated with a significant reduction in proliferative biomarkers PCNA and cyclins D1/B1. This tumor growth reduction was accompanied by the enhanced apoptotic cell death and an increase in Bax:Bcl2 ratio. The mechanism by which metformin manifests anti-tumor effects appears to be dependent on the inhibition of nuclear factor kappa B (NFkB) and mTOR signaling pathways. Decreased phosphorylation of NFkB inhibitory protein IKBα together with reduced enhancement of NFkB transcriptional target proteins, iNOS/COX-2 were observed. In addition, a decrease in the activation of ERK/p38-driven MAP kinase signaling was seen. Similarly, AKT signaling activation as assessed by the diminished phosphorylation at Ser473 with a concomitant decrease in mTOR signaling pathway was also noted as phosphorylation of mTOR regulatory proteins p70S6K and 4E-BP-1 was significantly reduced. Consistently, decreased phosphorylation of GSK3β which is carried out by AKT kinases was also observed. These results suggest that metformin blocks SCC growth by dampening NFkB and mTOR signaling pathways.
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DOI：
10.1158/1940-6207.capr-11-0266
发表时间：
2011-07
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Athar M;Kopelovich L
通讯作者：
Kopelovich L
DOI：
10.1158/1940-6207.capr-10-0375
发表时间：
2011-07
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Checkley LA;Rho O;Moore T;Hursting S;DiGiovanni J
通讯作者：
DiGiovanni J
影响因子：
11.5
作者：
Atzori, Francesco;Tabernero, Josep;Baselga, Jose
通讯作者：
Baselga, Jose
用PI3K/AKT/MTOR轴抑制剂治疗的晚期癌症患者的PIK3CA突变。
影响因子：
5.7
作者：
Janku F;Tsimberidou AM;Garrido-Laguna I;Wang X;Luthra R;Hong DS;Naing A;Falchook GS;Moroney JW;Piha-Paul SA;Wheler JJ;Moulder SL;Fu S;Kurzrock R
通讯作者：
Kurzrock R
DOI：
10.1158/1940-6207.capr-10-0175
发表时间：
2010-09
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Pollak M
通讯作者：
Pollak M