Scottish researchers discover how cancer cells cheat death

By Jenny Marra, Head of Press 01382 344910 j.m.marra@dundee.ac.uk

CANCER RESEARCH UK scientists in Scotland have uncovered a key signalling mechanism that may sustain cancer cells in the face of anti-cancer drugs, the prestigious journal Nature Cell Biology* reveals today (Tuesday).

It could explain how cancer cells shut down a cell suicide system normally used by the body to get rid of unhealthy, damaged or old cells.

Researchers at the University of Dundee believe that knowing exactly how cancer cells manage to override these signals and stay alive will help overcome resistance to treatments such as chemotherapy and radiotherapy, which work mainly by triggering cell suicide.

Cell suicide is one of the ways in which the body rejuvenates itself and stays healthy. When a cell detects something is wrong it sends a signal to the suicide machinery within the cell causing it to commit suicide. But many cancer cells are able to block the signals that tell them to die, depriving the body of one of its key defences against the disease.

Encouraging these suicidal tendencies in cancer cells is one of the main targets for cancer treatments.

The new research has found how a signalling molecule called ERK blocks one of the major pathways to cell suicide. Researchers discovered ERK causes an important chemical change in a molecule called caspase-9, which is involved in kick-starting a chain of events leading to cell suicide. ERK prevents caspase-9 from working and so allows cells to cheat death.

Cancer Research UK Senior Research Fellow Dr Paul Clarke, who led the team at the University of Dundee, says: "Many existing cancer treatments already work by promoting the chain of events leading to cell suicide, and resistance to treatment with anti-cancer drugs could be explained by survival signals from cancer cells overriding the drugs' effects. So there is a great deal to be gained by learning how the pathways leading to cell death actually work."

But while the findings pinpoint a mechanism that prevents cell death, doctors can't simply block the signalling process as it performs many important functions in normal cells.

Instead, treatments will need to take more specific action. Scientists will try to alter the way in which death molecules such as caspase-9 react to signalling molecules such as ERK, and so reopen the route to cell suicide.

Dr Clarke says: "By targeting specific points in the chain, we should be able to develop treatments that can overcome the problems of drug resistance."

He adds: "The next step will be experiments to block the actual molecular site where the signalling molecules interact with caspase-9. If that works, then blocking the same interaction in patients could prove an effective new tool against cancer."

Richard Sullivan, Cancer Research UK's Head of Clinical Programmes, says: "Learning as much as possible about the mechanisms controlling cell suicide will be essential for new targeted therapies."

"Also, many current cancer treatments kill cancer cells by activating cell pathways that are not understood in great detail. The more we learn about them, the more effective and less toxic we can make cancer treatments."

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 Nature Cell Biology Volume 5 Issue 7 (pp 647-654) July 2003