AMPK - ARE ACTIVATORS OR INHIBITORS REQUIRED FOR CANCER TREATMENT?

抄録

AMPK is activated by cellular energy stress and restores energy homeostasis by switching on ATP-producing catabolic pathways while switching off ATP-consuming processes. Early research suggested that AMPK activators might be efficacious in metabolic disorders such as Type 2 diabetes, and numerous activators with distinct mechanisms of action have been developed. AMPK is also activated by metformin, and is responsible for some but not all of its anti-diabetic effects. The discovery that activation of AMPK by energy stress required the tumour suppressor LKB1 introduced the first link between AMPK and cancer. Given that AMPK appeared to mediate many of the downstream effects of LKB1, that it inhibited cell growth and inhibition, and that use of metformin was associated with a lower incidence of cancer in diabetics, it was suspected that AMPK would be a tumour suppressor. Consistent with this, we have shown that T cell specific knockout of the PRKAA1 gene (encoding AMPK-alpha1) accelerates the development of T cell lymphomas caused by PTEN loss in mice. We have also shown that phenformin, the sister drug to metformin that was withdrawn from use in diabetes due to rare cases of lactic acidosis, provides protection against development of lymphoma in an AMPK-dependent manner, while metformin is not taken up by the tumour cells and fails to provide protection. Despite these results, analysis of the human cancer genome projects suggests that the PRKAA1 gene is quite frequently AMPLIFIED rather than mutated in solid tumours, particularly in adenocarcinoma of the lung where it is associated with mutations in p53. As a potential explanation, we have found that DNA-damaging agents activate AMPK in tumour cell lines by a mechanism independent of LKB1 that requires the alternate upstream kinase CaMKK2. Activation is triggered by increases in nuclear Ca2+, is specific for the alpha1 isoform, and appears to protect the cells against death induced by DNA damage. Thus, while AMPK may act as a tumour suppressor in leukemias and lymphomas, in solid tumours it may act instead as a tumour promoter, and AMPK inhibitors rather than activators might be useful for treating some cancers.