The Dundee team were looking for a protein that activates AMPK, an enzyme that reduces blood glucose levels and is a target for drugs commonly used in treating Type 2 diabetes.
They hoped that this protein would be a target for new anti-diabetes drugs, and their search ended with an enzyme called LKB1. Surprisingly, a lack of LKB1 is a known cause of Peutz-Jeghers syndrome, in which the risk of developing some cancers is 15 times higher than normal.
"It was totally unexpected," said Dario Alessi, one of the research team leaders. "LKB1 was thought of as a tumour suppressor gene, and AMPK was involved in diabetes. No one thought that there could be a link between the two."
Grahame Hardie, the second team leader, said: "The idea that LKB1 might switch on AMPK came from work I did on a related system in the simple single-cell organism brewer's yeast. [...] The idea that LKB1 might be the key was a genuine 'Eureka' moment, especially when I realised that Dario Alessi already worked on it and had all of the expertise necessary to test the idea."
Having identified the LKB1 enzyme in yeast, the Dundee team looked for its counterpart in rat liver extracts that could activate AMPK. They not only identified the rat version of LKB1, but also found two proteins that bind to LKB1 and enhance its activity. When the researchers removed LKB1 from the extract, they found that the extract could no longer activate AMPK, consistent with LKB1 being the activating enzyme.
LKB1 normally acts to prevent tumour growth. The way that it does this was unclear until now, but this research suggests that its tumour-preventing properties may be dependent on its ability to activate AMPK. This would make sense as active AMPK not only reduces blood glucose levels, but can also inhibit cell division and the production of molecules required for cell growth.
Patients with Type 2 diabetes commonly have high levels of glucose in their bloodstreams. Active AMPK reduces these by inducing muscles to take up glucose from the blood, and inhibiting glucose production. Some common anti-diabetes drugs target AMPK, increasing its activity. Intriguingly, the researchers found that one such drug, metformin, the active ingredient of the glucophage medicine, was ineffective in cells that contained no LKB1. Alessi said: "It is not yet clear whether metformin directly activates LKB1, our research didn't test this. It is one of the things to find out in the future." However, he believes that drugs which activate LKB1 could be more effective at treating diabetes than current therapies.
Although metformin would be ineffective against Peutz-Jeghers syndrome, as the tumours would not have any LKB1, virtually all other tumours retain their LKB1 activity. Alessi explains: "An exciting possibility is that metformin could be used for treating some forms of cancer. Metformin is the most widely used diabetes drug in the world. It will be interesting to see if people on metformin get less cancer - the data must be out there somewhere."
This press release is based on the following article:
Complexes between the LKB1 tumor suppressor, STRADa/b and MO25 a/b are upstream kinases in the AMP-activated protein kinase cascade.
Simon A Hawley, Jérôme Boudeau, Jennifer L Reid, Kirsty J Mustard, Lina Udd, Tomi P Mäkelä, Dario R Alessi and D Grahame Hardie.
Journal of Biology 2:28
Published 24th September 2003 16:00 GMT
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