‘Zombie caterpillars’ contain compounds of potential medical value

University of Dundee researchers have shown how a natural product derived from a group of fungi that have inspired horror novels, movies and computer games works to switch on a protein known to affect cancer cells.

Cordycepin is derived from fungi that infect insects or insect larvae. Among these is Ophiocordyceps sinensis, one of the most highly prized and expensive traditional Chinese medicines, which infects and slowly consumes caterpillars while they are living underground in Tibet. The fungus eventually forces its almost-dead hosts toward the surface, like zombies, before sending a spore-filled stalk out into the air.

The fungus has been used in China for centuries to boost the immune system and treat an array of diseases, including cancer. Demand has risen so fast in recent decades that it is now worth three times its weight in gold in some cities.

Cordycepin had previously been reported to activate the protein AMPK, the so-called ‘good cop/bad cop’ protein that is known to protect against cancer but can also exacerbate tumours in certain circumstances. However, it was not known how it did this.

Research led by Dr Simon Hawley and Professor Grahame Hardie, of the University’s School of Life Sciences, has now shown that cordycepin is converted inside cells into an analogue of AMP called cordycepin monophosphate (CoMP). It can, therefore, activate AMPK by mimicking the effects of its natural activator, AMP.

Professor Hardie warned that, due to its toxicity at concentrations only slightly higher than those required to activate AMPK, cordycepin is unlikely to have any medical application, except perhaps as a cytotoxic drug that kills cancer cells. However, that course of action would itself cause problems.

“There is currently a lot of interest in compounds derived from traditional Chinese medicine that activates 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, 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 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.

Professor Hardie and his colleagues have published their work in the latest edition of the journal Cell Chemical Biology. The research was funded by an Investigator Award from the Wellcome Trust.