UNC Scientists Find Key Mechanism By Which Cancer Cells Avoid Suicide

December 04, 1997

By DAVID WILLIAMSON
UNC-CH News Services

CHAPEL HILL -- A natural, normally beneficial protein called NF-kappa B teams up with a cancer gene to prevent cells in the body from killing themselves as they are supposed to after turning cancerous, researchers have discovered.

Using new drugs or other therapy, physicians might be able to prevent or control certain tumors by turning off or neutralizing that protein, the University of North Carolina at Chapel Hill School of Medicine scientists say.

"Our data show that activation of NF-kappa B suppresses activation of cell death that begins when a tumor gets started," said Dr. Albert S. Baldwin Jr., associate professor of biology at the UNC Lineberger Comprehensive Cancer Center. "Programmed cell death is a natural defense against cancer. NF-kappa B prevents cells in some tumor types from dying from this protective mechanism."

A report on the study appears in the Dec. 5 issue of the journal Science. Besides Baldwin, the senior investigator, authors are Dr. Marty W. Mayo, postdoctoral fellow at Lineberger; Cun-Yu Wang, a UNC Curriculum in Genetic and Molecular Biology graduate student; Patricia Cogswell, research technician; Dr. Kelley S. Rogers-Graham, a postdoctoral fellow; and Dr. Channing J. Der, professor of pharmacology, all at UNC. Dr. Scott W. Lowe, a Cold Spring Harbor Laboratories scientist, also participated in the work.

NF-kappa B is a major transcription factor -- a protein that attaches to DNA inside the nucleus of cells and turns genes on and off like a switch. In a Science article last year, the UNC-CH team reported finding that NF-kappa B prevents programmed cell death from occurring in some cancer cells even after they have been subjected to radiation, chemotherapy or another killing compound called tumor necrosis factor.

In the new experiments, the team reports on studies of a proto-oncogene -- a gene that can become cancerous -- called "ras", the most widely mutated gene of its kind and therefore the most intensively studied.

"Unmutated ras serves an absolutely essential function in all cells controlling normal growth and differentiation," Baldwin said. "For example, if you have a wound, you need cells to proliferate in a normal way. Ras is activated then but is ultimately turned off."

But in tumor cells, ras cannot be turned off and runs continuously like a stuck accelerator in a car, he said. Unless killed or removed, the tumor grows until the patient or animal dies.

The new experiments show that the mutated ras gene both elicits a killing response -- a call for cells to commit suicide -- and simultaneously overcomes that programmed cell death by activating NF-kappa B. The protein then protects the tumor by keeping the cells alive, allowing tumor growth.

Experiments show, however, that the killing response is still present in tumor cells and suggest it could be used to kill cancerous cells.

"This work, which we are very excited about and which would not have been possible without Dr. Der's collaboration, is offering us a window on what's going on inside the tumor cell," Baldwin said. "Potentially, it also provides an insight into therapy, at least for tumors that use NF-kappa B."

Nutritional compounds called flavonoids in fruits and vegetables and resveratrol in red wine -- both of which are known to help prevent cancer -- might work in part by blocking NF-kappa B, he said. Several pharmaceutical companies are developing NF-kappa B inhibitors.

The National Institutes of Health and the U.S. Army supported the research.

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Note: Baldwin can be reached at (919) 966-3652 or 966-3884.
Contact: David Williamson, (919) 962-8596.

University of North Carolina at Chapel Hill

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