Enzyme Discovery May Link Underlying Processes In Cancer And Heart Disease

Through their experiments with Mox1, one of the enzymes in the new class, the Emory scientists, led by biochemist J. David Lambeth, M.D., Ph.D., in collaboration with cardiology researcher Kathy Griendling, Ph.D., found that the reactive oxygen produced by the enzymes functions as a potent growth signal inside cells, instructing cells to divide more rapidly. Abnormal cell division or growth is seen in cancerous cells as well as in some forms of cardiovascular disease.

In the case of cancer, rapid and uncontrolled cell division leads to tumor formation. In cardiovascular disease, abnormal cell growth leads to the formation of plaques seen in hardening of the arteries (atherosclerosis) and in thickening of the blood vessel walls, which causes high blood pressure. Although scientists know that different molecular signals instruct cells to behave in various ways, the cellular mechanisms regulating cell growth have been poorly understood.

Dr. Lambeth and his colleagues first cloned the human Mox1 gene based on its similarity to an enzyme that generates reactive oxygen in neutrophils as a mechanism to kill bacteria. They then introduced the Mox1DNA into mouse cells and were surprised to observe that the cells took on the appearance of cancer cells and divided more rapidly than normal cells. When they injected these transformed cells into mice they found that the cells were extremely powerful in producing tumors.

"Although scientists have known that reactive oxygen is produced by many cancer cells, they have not known whether it is a cause of cancer," Dr. Lambeth says. "These studies show that the reactive oxygen can be a cause rather than a byproduct of cancer and that the Mox1 enzyme or a close relative is the source of the reactive oxygen."

The scientists found that Mox1 also is present in the walls of arterial cells, where it regulates normal cell growth. An overabundance of the enzyme, however, occurs under conditions that lead to hypertension and atherosclerosis, suggesting that Mox1 or other enzymes in its class may be involved in these abnormal processes.

The research also demonstrated that the abnormal cell growth directed by the Mox1 family can be reversed by treatments that remove reactive oxygen from cells. This suggests, says Dr. Lambeth, that novel approaches might be developed to treat cancer, reverse hardening of the arteries or treat high blood pressure, including drugs designed to block this type of enzyme or treatments that destroy reactive oxygen.

Irwin Fridovich, Ph.D., James B. Duke Professor of Biochemistry at Duke University Medical Center, who discovered an enzyme that "detoxifies" reactive oxygen, believes the Emory research will likely lead scientists to try to clarify the specific signaling roles of reactive oxygen and hydrogen peroxide. "One cannot help feeling that we are getting close to knowing how to most usefully intercede in treating and reversing diseases involving abnormal cell proliferation," he notes.

"The discovery of Mox1 by Drs. Lambeth and Griendling and their colleagues could be fundamentally important in developing a new understanding of causes of diseases ranging from cancer and heart disease to stroke and dementia," says Emory cardiologist R. Wayne Alexander, M.D. "These findings could open the door to exciting new approaches to treatment of these common maladies."

The Emory research was funded by the National Institutes of Health.