The findings, published in EMBO Reports [1] and presented by Cancer Research UK's chief scientist Professor Sir David Lane at the NCRI Cancer Conference in Birmingham recently, pave the way for the development of a new range of cancer treatments. The study, which was carried out at the University of Dundee, examined a molecule called NEDD8, which is known to have important role in turning on p53 (the gene that inhibits a cell's growth). p53 is faulty (and sometimes missing) in more than half of cancers.
The team, led by AICR Research Fellow, Dr Dimitris Xirodimas, discovered that blocking the activity of NEDD8 played a crucial part in enabling cancer drugs such as Actinomycin D* to switch on p53 – causing the death of the cancer cells.
NEDD8 works by attaching itself to other proteins – a process called NEDDylation – to alter their properties. The Dundee group found that NEDDylation stops certain proteins leaving a specialized area of the cell; impeding this allows the proteins to move and gives the signal for p53 to be activated, killing the cancer cells.
Dr Xirodimas said: ‘We are excited about these findings. A pharmaceutical company has recently developed chemicals which block the NEDDylation reaction and these compounds are currently being tested in clinical trials for the treatment of cancer. Our research reinforces the value of this work and opens up avenues for the development of new ways to treat cancer.’ The study was funded by AICR, the Association for International Cancer Research.
The charity's Scientific Advisor, Dr Mark Matfield, said: ‘The significance of this discovery is that it could lead to drugs that would be effective against a wide range of cancers. Over the last decade, many of the new cancer drugs have only been useful for a few, specific cancers. What we really need are effective broad range cancer therapies.’ Professor Sir David Lane said: ‘p53 is missing or faulty in almost half of all cancers and there are 270,000 new cases of cancer in the UK each year so by understanding potential therapies can switch it on and off is an important part of the search for new potential therapies.’
* Actinomycin D or Dactinomycin is used to treat sarcomas, Wilm's tumour, germ cell cancers (testicular cancer), melanoma and choriocarcinoma. Low doses of actinomycin D cause disruption of the nucleolus, which is a distinct compartment within the cell nucleus.
[1] Sundqvist, A. et al. (2009) Regulation of nucleolar signalling to p53 through NEDDylation of L11. EMBO Reports 10, 1132–1139