Controlling cancer's life/death choice
Cancer Research UK scientists have discovered how some cancer cells choose to live and others die following anti-cancer treatment, unveiling their findings in the prestigious journal PNAS1.
Most cancer cells trigger cell death in response to chemotherapy but some opt to stall their growth to keep themselves alive.
Researchers found a protein molecule called p300 was key in determining the fate of tumours hit with anti-cancer treatments.
Experts believe blocking the action of the molecule could help increase the sensitivity of cancers to chemotherapy and may lead to ways to predict which patients will respond to treatment.
Scientists knew p300 was involved in regulating a gene called p53 - known as the guardian of the genome.
The gene protects normal cells from the effects of DNA damage that could lead to cancer. If cells look like they may turn cancerous p53 suspends their growth or triggers their suicide mechanism.
Anti-cancer drugs, which work by damaging DNA, exploit this mechanism in cancer cells with an intact p53 gene. When tumours are exposed to chemotherapy p53 is activated so that the cancer cell dies or stops growing. But what determines whether the cancer cell is successfully killed off or just put to sleep has remained unclear until now.
Study author Professor Carlos Caldas, from the Cancer Research UK Department of Oncology at the University of Cambridge, says: "Chemotherapy works by damaging the DNA in cancer cells and triggering cell death. But some cancer cells are resistant to treatment and fail to die.
"It seems that cancer cells make a choice between life and death when attacked with chemotherapy. Finding out how this process is controlled will help us design ways to make anti-cancer drugs more effective in treating the stubborn forms of the disease."
In the new study researchers compared the effect of UV radiation on human cancer cells that had p300 and those that were missing the molecule. They found that cells with p300 only partially activated p53 and stopped growing but remained alive. However, cells without p300 could fully activate p53 and trigger their suicide mechanism in response to DNA damage.
The team also tested the effect of a number of chemotherapy agents on cells with and without p300 and found the same effect: cells with p300 frequently failed to die whereas identical cells lacking p300 triggered their suicide machinery.
Prof Caldas says: "The molecule seems to safeguard cancer cells from the effects of chemotherapy. Designing drugs to target p300 and block its action could make current anti-cancer drugs more potent particularly against the resistant forms of the disease.
"We could also use the molecule as a way to predict whether tumours will be responsive to chemotherapy prior to treatment," he adds.
Prof Caldas is currently running a large study to determine if the combined analysis of p53 and p300 status in patients' tumours could be used to determine prognosis.
Professor Robert Souhami, Director of Clinical and External Affairs at Cancer Research UK, says: "Chemotherapy is a very effective way of killing tumours but there are some cancer cells that are resistant to treatment. We need new approaches to tackle these difficult forms of the disease and targeting this molecule looks like a promising approach."
- Proceedings of the National Academy of Science101 (17)