From life to death at the flick of a switch

Turning a vital component of cancer cells from bodyguard to assassin could form the basis of new cancer treatments, according to a report published this week¹.

Scientists in the Cancer Research UK Oncology Unit at Southampton University studied a molecule with a key role in protecting the cells of lymphomas – cancers of the immune system that affect adults and young people – from early death.

The researchers found that this molecular bodyguard can be rapidly transformed into a cell killer. The discovery of this lethal switch could lead to new treatments for lymphoma and other forms of cancer.

Dr Graham Packham, leading the team at the Cancer Research UK Oncology Unit, says: “There are many different forms of lymphoma, some of which do not respond very well to current chemotherapy. We now have an exciting target for developing new lymphoma treatments. Recent studies suggest it has potential for treating other types of cancer as well.

“If we can knock out this molecular bodyguard, or switch it to its deadly form, we can kill cancer cells from the inside. However, we also need to find out more about its function in healthy cells.”

The molecule is called Mcl-1 and it has a vital role in keeping cell numbers at a healthy level. Cells are pre programmed to have a limited lifespan in order to allow old cells to be continually replaced by new growth. The time of death is carefully controlled, and Mcl-1 is required to protect cells from being killed too soon.

This research shows that lymphoma cells typically have high levels of Mcl-1, and that this is important for keeping them alive longer than usual. Failure of cell death mechanisms leads to increased cell numbers and the development of tumours. It also strengthens resistance to radiotherapy and drugs that work by triggering cell death.

The team used cisplatin, an anticancer drug, to kill lymphoma cells in the laboratory, and tracked the role of Mcl-1 throughout the death process.

The results show that Mcl-1 is split in two during cell death, removing the cell’s protection. But the researchers also found that one of the leftover fragments itself actively promotes cell death.

The fragment activates several cell death pathways. It also causes more and more of the protective Mcl-1 to be switched into the same lethal form. This creates a positive feedback loop that drives the cell inexorably towards death.

Professor Robert Souhami, Director of Clinical and External Affairs at Cancer Research UK, says: “Cancers employ many different strategies to keep themselves alive and to avoid the effects of anticancer drugs.

“This study tells us much more about how cell death is controlled in healthy cells and some malignant cells, and provides potentially exciting leads for new treatment.

“The research suggests a way to switch cell death mechanisms back on in defective cells. If we can develop the means to do this when and where we choose, the potential will be enormous.”

ENDS

1. Oncogene23 pp.4818-4827