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 tumor promoter and suppressor. Ana Chocarro-Calvo, while she was a post-doc in Professor Colin Goding’s lab at Ludwig Oxford, and Maria Gutiérrez-Salmerón from Prof. Custodia García-Jiménez´s lab at University Rey Juan Carlos in Madrid have now answered why it appears to play such opposing roles in a study published in 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 cell proliferation. It does so by regulating the activity of EP300, an enzyme that helps control the expression of genes. Notably, glucose-mediated activation of AMPK drives EP300 activity towards genes that are also regulated by a colorectal cancer oncogene known as b-catenin. Goding, Chocarro-Calvo and colleagues discovered that glucose metabolism activates AMPK through its 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 known as glycogen. In other types of cancer, the ability to make glycogen suppresses ROS-mediated activation of AMPK in response to glucose. Normal colon cells do make glycogen, but this ability is lost during tumour evolution—allowing glucose to activate AMPK and drive proliferation.
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.