AMPK Activator extracted from Insect-digesting Fungus

Research led by Dr Simon Hawley and Professor Grahame Hardie, at the University of Dundee’s School of Life Sciences, has revealed how cordycepin, a natural product derived from a group of fungi, can switch on a protein known to affect cancer cells.

The group of fungi under study included Ophiocordyceps sinensis, a highly prized and expensive traditional Chinese medicine, which infects and slowly consumes caterpillars while they are living underground.  “There is currently a lot of interest in compounds derived from traditional Chinese medicine that activate AMPK, with around 150 papers published on this subject in 2019 alone,” said Professor Hardie. “Chinese traditional medicine is big business and many researchers are looking to explain the effects of these medicines on a more rigorous scientific basis. It is important to understand how natural products marketed as treatments for a range of conditions actually work.

“We studied cordycepin, which is extracted from fungi that infect the larvae of insects such as caterpillars, turning them into ‘zombies’ that are forced to crawl towards the surface, where the fungus finally kills the caterpillar and sends out a fruiting body above the ground. Several horror novels, a film and a computer game have been based around the idea that a mutant version of this fungus might infect humans and turn them into zombies!

“In our paper we show that cordycepin activates AMPK in cells because it is converted to CoMP (cordycepin monophosphate) which mimics the effects of the natural activator, AMP.

AMPK normally acts as a tumour suppressor but if, despite its best efforts, a tumour does arise, then it can switch to being a tumour promoter instead. This may occur because AMPK protects the tumour cells against the stresses that occur due to their rapid cell growth and division and poor blood supply. This AMPK helps the abnormal cancer cells to survive rather than die.

“In the context of cancer treatment, then, the fact that cordycepin activates AMPK could be regarded as a bad thing because it would protect the cancer cells. In our paper we suggest that if cordycepin was used for chemotherapy, it might be necessary to use it with an AMPK inhibitor.”

AMPK was first defined by Professor Hardie in Dundee in the 1980s. In 2003, Professor Hardie and his colleague, Professor Dario Alessi, showed that another protein called LKB1 was required to switch on AMPK. Mutations in the LKB1 gene were known to cause an inherited predisposition to cancer in humans called Peutz-Jeghers Syndrome and it was these findings that established a link between AMPK and cancer for the first time.

This research was funded by an Investigator Award from the Wellcome Trust and published in Cell Chemical Biology