Metformin transiently inhibits colorectal cancer cell proliferation as a result of either AMPK activation or increased ROS production.
Metformin transiently inhibits colorectal cancer cell proliferation as a result of either AMPK activation or increased ROS production.
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DOI：
10.1038/s41598-017-16149-z
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发表时间：
2017-11-22
影响因子：
4.6
通讯作者：
Gariboldi M
中科院分区：
文献类型：
--
作者：
Mogavero A;Maiorana MV;Zanutto S;Varinelli L;Bozzi F;Belfiore A;Volpi CC;Gloghini A;Pierotti MA;Gariboldi M
二甲双胍是一种广泛使用且耐受性良好的抗糖尿病药物，可降低癌症风险，改善某些恶性肿瘤的预后。然而，其抗癌作用的机制仍不清楚。以结直肠癌细胞株HT29、HCT116和HCT116、−/−细胞为研究对象，研究了二甲双胍对结直肠癌的抗癌作用。二甲双胍通过诱导细胞周期停滞于G0/G1期，从而减少细胞增殖和迁移。伴随着c-Myc表达的急剧下降和IGF1R的下调。二甲双胍的抗增殖作用是通过两种不同的机制实现的：激活AMPK和增加活性氧的产生，从而抑制mTOR通路及其下游靶点S6和4EBP1。CD44和LGR5表达的减少表明该药物对具有干细胞特征的肿瘤细胞有作用。然而，克隆形成分析显示，二甲双胍减缓了细胞形成克隆的能力，而不会阻止细胞生长，这一点得到了证实，即没有细胞凋亡、自噬或衰老。我们的研究发现，二甲双胍只能短暂地抑制结直肠癌细胞的生长，这表明应该努力寻找与双胍结合可以协同作用诱导细胞死亡的化合物。
Metformin is a widely used and well-tolerated anti-diabetic drug that can reduce cancer risk and improve the prognosis of certain malignancies. However, the mechanism underlying its anti-cancer effect is still unclear. We studied the anti-cancer activity of metformin on colorectal cancer (CRC) by using the drug to treat HT29, HCT116 and HCT116 p53−/− CRC cells. Metformin reduced cell proliferation and migration by inducing cell cycle arrest in the G0/G1 phase. This was accompanied by a sharp decrease in the expression of c-Myc and down-regulation of IGF1R. The anti-proliferative action of metformin was mediated by two different mechanisms: AMPK activation and increase in the production of reactive oxygen species, which suppressed the mTOR pathway and its downstream targets S6 and 4EBP1. A reduction in CD44 and LGR5 expression suggested that the drug had an effect on tumour cells with stem characteristics. However, a colony formation assay showed that metformin slowed the cells’ ability to form colonies without arresting cell growth, as confirmed by absence of apoptosis, autophagy or senescence. Our finding that metformin only transiently arrests CRC cell growth suggests that efforts should be made to identify compounds that combined with the biguanide can act synergistically to induce cell death.
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DOI：
10.1016/j.bbrc.2015.03.178
发表时间：
2015-05-22
影响因子：
3.1
作者：
Kato, Haruo;Sekine, Yoshitaka;Suzuki, Kazuhiro
通讯作者：
Suzuki, Kazuhiro
MIF/CD74轴是结肠癌的新疗法的靶标。
DOI：
10.1186/s13046-016-0475-z
发表时间：
2017-01-23
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Bozzi F;Mogavero A;Varinelli L;Belfiore A;Manenti G;Caccia C;Volpi CC;Beznoussenko GV;Milione M;Leoni V;Gloghini A;Mironov AA;Leo E;Pilotti S;Pierotti MA;Bongarzone I;Gariboldi M
通讯作者：
Gariboldi M
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：
5.8
作者：
Biswas, S;Chida, AS;Rahman, I
通讯作者：
Rahman, I
影响因子：
6.4
作者：
Lee, Jin Ha;Kim, Tae Il;Kim, Won Ho
通讯作者：
Kim, Won Ho