Important role of the LKB1-AMPK pathway in suppressing tumourigenesis in PTEN deficient mice
Résumé
The LKB1 tumour suppressor phosphorylates and activates AMPK when cellular energy levels are low, thereby suppressing growth through multiple pathways, including inhibiting the mTORC1 kinase that is activated in the majority of human cancers. Blood glucose lowering type-2 diabetes drugs also induce LKB1 to activate AMPK, indicating that these compounds could be used to suppress growth of tumour cells. In this study we investigated the importance of the LKB1-AMPK pathway in regulating tumourigenesis in mice resulting from deficiency of the PTEN tumour suppressor, which drives cell growth through over-activation of the Akt and mTOR kinases. We demonstrate that inhibition of AMPK resulting from a hypomorphic mutation that decreases LKB1 expression does not lead to tumourigenesis on its own, but markedly accelerated tumour development in PTEN+/- mice. In contrast, activating the AMPK pathway by administration of PTEN+/- mice metformin, phenformin or A-769662, significantly delayed tumour onset. We demonstrate that LKB1 is required for activators of AMPK to inhibit mTORC1 signalling as well as cell growth in PTEN deficient cells. Our findings highlight in an animal model relevant to understanding human cancer, the vital role that the LKB1-AMPK pathway plays in suppressing tumourigenesis resulting from loss of PTEN tumour suppressor. They also suggest that pharmacological inhibition of LKB1 and/or AMPK would be undesirable, at least for the treatment of cancers in which the mTORC1-pathway is activated. Most importantly our data demonstrate the potential of AMPK activators such as clinically approved metformin as anti-cancer agents, which will suppress tumour development by triggering a physiological signalling pathway that potently inhibits cell growth.
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