University of Dundee

The Strange Case of AMPK and Cancer: Dr Jekyll or Mr Hyde?

10 Jul 2019

Prof. Grahame Hardie and two of his co-workers, Diana Vara-Ciruelos and Fiona Russell, have published a review in the journal Open Biology with a title inspired by the classic novella by the Scottish author Robert Louis Stevenson. Their article discusses the controversial role in cancer of AMP-activated protein kinase (AMPK), which was first defined and named by Prof. Hardie at the University of Dundee in the late 1980s.

AMPK is a protein kinase, a protein that modifies other proteins by the addition of phosphate groups, thus changing their function. It is known to be switched on by stresses that deplete the energy status of cells. Prof. Hardie takes up the story: “We had originally thought that AMPK would always protect against the development of cancer, because it inhibits cell growth and proliferation and (as discovered by Dario Alessi and myself in 2003) mediates many of the effects of a well-established tumour suppressor called LKB1. Consistent with this idea, the effect of genetic loss of AMPK in mice before cancer has occurred suggests that its presence protects against the development of the disease. Paradoxically, however, the effect of genetic loss of AMPK after cancer has occurred shows that under those circumstances its presence exacerbates the cancer”. Thus, once cancer has arisen AMPK switches from being a tumour suppressor to a tumour promoter (like the switch in Stevenson’s novel from the benevolent Dr Jekyll to the malevolent Mr Hyde, who were in fact the same person). Prof. Hardie says: “The tumour-promoting effects of AMPK most likely occur because it protects the tumour cells against stresses caused by their rapid growth. AMPK acts to protect the cells in which it is located, irrespective of whether those cells are normal or cancerous”.

One implication of this research is that drugs that activate AMPK (several of which are already available) might provide protection against cancer before it has occurred while, conversely, drugs that inhibit AMPK might be useful for treatment of cancer once it has arisen. Prof. Hardie now plans to use model systems to test these predictions.

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