Elevated basal AMP-activated protein kinase activity sensitizes colorectal cancer cells to growth inhibition by metformin

Abstract

Expression and activity of the AMP-activated protein kinase (AMPK) α 1 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 AMPK α 1 signalling. We have therefore attenuated mammalian target of rapamycin (mTOR) control of AMPK α 1 to generate a mutant colorectal cancer in which AMPK α 1 signalling is elevated because AMPK α 1 serine 347 cannot be phosphorylated by mTORC1. The elevated AMPK α 1 signalling in this HCT116 α 1.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 AMPK α 1 kinase was deleted. We conclude that elevated AMPK α 1 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 AMPK α 1 activation for patient stratification could herald a place for the well-tolerated drug metformin in colorectal cancer therapy.