BioWorld International Correspondent
LONDON - New cancer therapies could spring from a better understanding of how a molecule that helps cancer cells stay alive can convert into one that kills them. The molecule, called Mcl-1, normally plays a role in keeping cell numbers at the right level and is present at high levels in lymphomas - cancers of blood cells.
Researchers at the Cancer Research UK Oncology Unit at Southampton University found that Mcl-1 can act as a molecular switch in lymphoma cells. In one form it helps the cancer cells survive, but when split by cellular enzymes, one of the fragments that result drives the cell toward apoptosis.
Graham Packham, reader in cancer services at Southampton University, told BioWorld International: "We have identified a potential new therapeutic target for lymphomas, some of which do not respond very well to current chemotherapy."
He said other studies suggested that treatments targeting Mcl-1 could be developed for other cancers, as well.
"Many other cancers express Mcl-1, including breast cancer," he said. "But it is also found in various normal cells, such as normal lymphocytes, at some stages of their lives, so we need to investigate whether interfering with Mcl-1 may lead to toxic side effects."
Robert Souhami, director of clinical and external affairs at Cancer Research UK, which funded the study, said: "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."
Packham and his colleagues describe their study in a paper in the May 3, 2004, issue of Oncogene. The paper is titled "Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage."
Mcl-1 is a member of the Bcl-2 family of proteins. Bcl-2, the first to be identified, is known to be activated in lymphomas as a result of mutation, and about half of all cancers express it at high levels. Abnormalities in Bcl-2 might play a role in triggering cancer and in making cancer cells resistant to chemotherapy and radiation.
Packham's group decided to investigate members of the Bcl-2 family that were structurally similar to Bcl-2 itself. They focused on Mcl-1 and were able to show that lymphomas have high levels of the protein. If they interfered with the expression of Mcl-1 in lymphoma cells using antisense oligodeoxynucleotides, the cells died.
"We can conclude from this that Mcl-1 is a survival protein that is required to keep these cells alive," Packham said.
The group also examined Mcl-1 when they induced apoptosis in lymphoma cells with cisplatin, a chemotherapeutic drug. Packham said: "We found that Mcl-1 is cleaved by a protease during cell death, and that this converts it from being a survival protein into a protein that is very efficient at killing cells. We think this conversion may cause more and more of the protective Mcl-1 to be switched into the same lethal form, creating a positive feedback loop that efficiently drives the cell along the pathway toward cell death."
Although other studies had shown that knocking out Mcl-1 in certain cancers, such as multiple myeloma, could lead to apoptosis, this is the first study to demonstrate Mcl-1's role as a molecular switch, flicking between survival protein and killer molecule.
If researchers find drugs that can interfere with the function of Mcl-1 or that are able to switch Mcl-1 from a survival protein into a killer protein, that could lead to more effective therapies for cancers such as lymphomas, Packham added.
The team now is examining the expression of Mcl-1 in different kinds of lymphomas, to find out whether people whose tumors have higher levels of it respond differently to chemotherapy, or whether they have higher-grade lymphomas. Packham and his colleagues also hope to pursue work on identifying molecules that target Mcl-1, which could form the basis for developing new drugs to treat some cancers.