Researchers Identify Protein That Kills Cancer Cells

The study appears in the Jan. 17 issue of the journal Molecular Cell. The researchers found that CUGBP2 helps regulate production of cyclooxygenase-2, (COX-2), which is better known as a key culprit in arthritis.

"The gene that produces COX-2 is turned on very early in cancer, so there has been a lot of research to see whether interfering with it might be an effective therapy," says principal investigator Shrikant Anant, Ph.D., assistant professor of medicine in the Division of Gastroenterology and research member of the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis.

In rheumatoid arthritis, COX-2 converts arachidonic acid in the body into prostaglandins. In cancer cells, COX-2 levels also rise and trigger production of prostaglandins. The prostaglandins bind to tumor cells and help turn on genes involved in the generation of new blood vessels, helping feed the cells' rapid growth.

In this study, Anant and colleagues looked at events early in the development of tumors. In any cell's life, there is a normal cycle of replication and division. First, a close copy of DNA, called RNA is made, and that RNA, in turn is translated into proteins. These proteins have to be made at precisely the right time in order for the cycle to work correctly. It is thought that tight regulation of important proteins is critical, and interfering with the strict regulation of these proteins even by a few minutes can lead to serious problems such as cancer.

That precise timing is controlled by the activity of messenger RNA (mRNA). Anant and colleagues explored the interaction of CUGBP2 with COX-2 mRNA in eight types of human cancer cells. In all eight, levels of CUGBP2 were very low.

"This suggests that an important step in the development of cancer is turning down the gene responsible for production of CUGBP2, thereby reducing CUGBP2 protein levels and allowing the cancer to flourish," Anant explains.

The researchers also found that when CUGBP2 attached to mRNA from COX-2, cancer cells no longer could make COX-2, and they died. That suggested that CUGBP2 might play a central role in tumor cell survival or death.

"CUGBP2 may be one type of master switch used by the cell to control other key proteins," says co-author Brian K. Dieckgraefe, M.D., Ph.D., assistant professor of medicine in the Division of Gastroenterology. "Proteins like COX-2 need to be tightly regulated to avoid uncontrolled growth. That may be why CUGBP2 levels were significantly lower in every single tumor we studied."

Anant, Dieckgraefe and colleagues also found that CUGBP2 was not toxic to healthy cells. Moreover, when they introduced CUGBP2 into cancer cells at the levels found in normal cells, the cancer cells died.

"When CUGBP2 is introduced, there are a number of molecular derangements that take place in the cancer cell that make it susceptible to death," Anant says. "In the future, it may be possible to use this protein as a means of killing tumor cells without harming normal cells because normal cells already produce significant amounts of the protein."

Anant already is looking at whether it is possible to use the protein in animal models of cancer to see whether it has the same effect in their tumors as it did in human cancer cells in the test tube. If these studies continue to demonstrate that it's possible to kill cancer cells by raising CUGBP2 levels, Anant believes the strategy might be ready for human testing in a few years.

Even if raising levels of CUGBP2 does not eliminate cancer, the researchers believe it may help existing therapies work better.

"Most therapeutic tools we currently use for cancer act by triggering cells to self-destruct," Dieckgraefe says. "So it's entirely possible that this might become a synergistic addition to existing therapies. By augmenting existing chemotherapy with CUGBP2, we might be able to make traditional therapies more effective."

In addition, the team says COX-2 might not be the only protein that CUGBP2 influences. Anant and Dieckgraefe say broad ranges of proteins have similar targets, so they believe CUGBP2 may have a role in regulating the production of those proteins, too.

###Mukhopadhyay D, Houchen CW, Kennedy S, Dieckgraefe BK, Anant S. Coupled mRNA stabilization and translational silencing of cyclooxygenase-2 by a novel RNA binding protein. Molecular Cell, vol. 11:1, pp. 113-126, Jan. 17, 2003.

This research was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health, and from the Foundation for Digestive Health and Nutrition of the American Gastroenterology Association.