AMP激活蛋白激酶（AMPK）α1催化亚基的表达和活性与结直肠癌患者的不良预后显著相关。因此，人们极为关注从AMPKα1信号的肿瘤性升高中发现信号漏洞的可能性。我们因此抑制哺乳动物雷帕霉素靶点(mTOR)对AMPKα1的控制，从而产生了一种突变的结直肠癌，其中AMPKα1信号升高，因为AMPKα1谷氨酸347无法被mTORC1磷酸化。这种HCT116α1.S347A细胞系中增强的AMPKα1信号使其对二甲双胍（Metformin）的生长抑制产生了高敏感性。补充的化学方法在HCT116和基因上有所不同的HT29结直肠细胞中证实了这种关系，因为AMPK激活剂在两种细胞系中都对二甲双胍的生长抑制产生了易感性。当AMPKα1激酶被删除时，二甲双胍的生长抑制就会被取消。我们得出结论，AMPKα1活性的升高以这样一种方式修改了信号架构，以至于二甲双胍治疗会损害细胞增殖。这种突变的HCT116 AMPKα1-S347A细胞系不仅为未来的研究提供了宝贵的资源，而且我们的研究结果表明，AMPKα1激活的稳健生物标志物可能为慢性AMPKα1激活的患者分层带来希望，同时也为耐受良好的二甲双胍药物在结直肠癌治疗中找到了位置。

Expression and activity of the AMP-activated protein kinase (AMPK) α1 catalytic subunit of the heterotrimeric kinase significantly correlates with poor outcome for colorectal cancer patients. Hence there is considerable interest in uncovering signalling vulnerabilities arising from this oncogenic elevation of AMPKα1 signalling. We have therefore attenuated mammalian target of rapamycin (mTOR) control of AMPKα1 to generate a mutant colorectal cancer in which AMPKα1 signalling is elevated because AMPKα1 serine 347 cannot be phosphorylated by mTORC1. The elevated AMPKα1 signalling in this HCT116 α1.S347A cell line confers hypersensitivity to growth inhibition by metformin. Complementary chemical approaches confirmed this relationship in both HCT116 and the genetically distinct HT29 colorectal cells, as AMPK activators imposed vulnerability to growth inhibition by metformin in both lines. Growth inhibition by metformin was abolished when AMPKα1 kinase was deleted. We conclude that elevated AMPKα1 activity modifies the signalling architecture in such a way that metformin treatment compromises cell proliferation. Not only does this mutant HCT116 AMPKα1-S347A line offer an invaluable resource for future studies, but our findings suggest that a robust biomarker for chronic AMPKα1 activation for patient stratification could herald a place for the well-tolerated drug metformin in colorectal cancer therapy.