Better understanding of cell signalling helps cancer research

A team led by Dr David Huang from The Walter and Eliza Hall Institute of Medical Research (WEHI) has made significant advances in understanding the signalling pathways that affect the behaviour of cells. This discovery may assist in the eventual development of more refined therapies to combat a range of cancers, including blood-borne cancers such as lymphomas.

Under normal conditions of health, a process called apoptosis - or programmed cell death - ensures that old, damaged or unnecessary cells die at the right time. This process is essential to maintain a balance of normal cells required for good health.

Scientists have been aware that the balance between two competing classes of proteins - pro-survival and anti-survival - determines whether a cell lives or dies. It has been understood that the pro-survival proteins keep cells alive. When a cell is damaged or is no longer required, the anti-survival proteins act upon the pro-survival proteins to trigger cell death. If this normal and healthy program is faulty, then damaged cells persist and continue to divide uncontrollably, creating rogue collections of cells or cancer. Therefore, an attractive way to kill cancer cells may be to tip the balance against the pro-survival proteins, such as by harnessing the action of the anti-survival proteins. However, a potential danger of using anti-survival cells to kill cancer cells is the collateral damage to normal cells.

The WEHI team has discovered that the process is not as simple as "pro- versus anti-survival." Instead, they discovered that some of the anti-survival proteins have highly selective action on particular pro-survival proteins. This discovery of the cell's complexity will be useful in the eventual development of more specific cancer drugs that have fewer side effects.

Dr Huang explains that the discovery about how cell death proceeds is already having a practical impact in the research laboratories of WEHI. The techniques of Nuclear Magnetic Resonance (NMR) and X-ray crystallography are being used to search for the detailed mechanism that drives the selective action of anti-survival proteins. When this is defined, it may help in developing more effective cancer treatments.

Other members of the discovery team are Dr Lin Chen, Mr Simon Willis, Dr Andrew Wei, Professor Jerry Adams, Professor Peter Colman, Dr Brian Smith, Dr Jamie Fletcher, Dr Mark Hinds (all from WEHI) and Dr Catherine Day from the Biochemistry Department, University of Otago, Dunedin, New Zealand.

The research was funded by the NHMRC; Cancer Council Victoria; the US-based Leukemia and Lymphoma Society; the Australian Cancer Research Foundation (ACRF); the Viertel Foundation; the Leukaemia Foundation of Victoria; and the Marsden Fund (New Zealand).

The research paper is published in the prestigious journal Molecular Cell of 4 February 2005. A related article describing the structure of one of the pro-survival proteins, determined by Dr Catherine Day and Dr Mark Hinds, appears in the 11 February 2005 issue of the Journal of Biological Chemistry.



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