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Professor Colin Goding and colleagues reveal that a distinct metabolic environment in colon cancer cells allows AMPK to be activated by glucose to drive cancer proliferation, with implications for AMPK-targeting cancer drugs.

AMPK is a master regulator of cell metabolism that has been identified as both a tumour promoter and suppressor. Ana Chocarro-Calvo, while she was a post-doc in Professor Colin Goding’s lab at Ludwig Oxford, together with Maria Gutiérrez-Salmerón from Prof. Custodia García-Jiménez´s lab at University Rey Juan Carlos in Madrid have now answered why AMPK appears to play such opposing roles in a study published in the journal PLOS Biology.

AMPK is ordinarily activated when levels of the sugar glucose decline in cells. The researchers found that in colon cancer cells, but not other cancer types, AMPK is activated in response to glucose to promote colorectal cancer proliferation. It does so by regulating the activity of EP300, a key acetyltransferase and transcriptional regulator that helps control the expression of genes. Notably, glucose-mediated activation of AMPK drives EP300 activity towards genes that are also regulated by the colorectal cancer oncogene, b-catenin. Goding, Chocarro-Calvo and colleagues discovered that glucose metabolism activates AMPK through the generation of reactive oxygen species (ROS), but this only occurs in colon cancer cells that are unable to store glucose as a more complex carbohydrate called glycogen. In other cancer types, the ability to make glycogen suppresses ROS-mediated activation of AMPK in response to glucose. Importantly, normal colon cells do make glycogen, but this ability is lost during tumour evolution, allowing glucose to activate AMPK and drive proliferation via EP300.

Given the importance of drugs, such as metformin, that target AMPK in diabetes and cancer, the differential ability of cells to store glucose as glycogen may guide the future choice of AMPK-targeting therapies for specific cancer sub-types.

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