Because of its protective function in the body, the protein potentially could be used to selectively shield cells from toxic therapies, according to senior author Steven J. Weintraub, M.D., an investigator with the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital.
The protein, called Bcl-xL, has the ability to help keep cells alive, but does so by interfering with programmed cell death, or apoptosis, a process that can rid the body of unwanted or damaged cells.
"We earlier found that Bcl-xL helps the body's healthy cells survive the effects of toxic chemotherapeutic agents," says Weintraub, assistant professor of surgery and of cell biology and physiology. "This new study clearly demonstrates a trade-off by showing that normal levels of Bcl-xL encourage the growth of tumors in mice exposed to a carcinogen."
The study, appearing in Oncogene's advance online publication, compared the effect of urethane, a lung-specific carcinogen, on two sets of mice: wild-type mice, which have two functional genes that express Bcl-xL, and transgenic mice that have only one functional gene expressing Bcl-xL. Because they have only one of the genes, the transgenic mice produce less Bcl-xL.
After exposure to urethane, 40 percent of wild-type mice developed seven or more lung tumors, while no transgenic mice developed more than seven tumors. Furthermore, wild-type mice on average had larger tumors than transgenic mice.
"In light of the detrimental effect of normal Bcl-xL levels in terms of tumor growth, we wanted to carefully assess the protein's beneficial effect--its ability to deal with typical cellular toxins," Weintraub says.
The research team looked at sets of the same type of mice as in the previous experiments, this time examining liver cell damage resulting from a regimen that mimicked a three-day alcoholic binge. In this case, wild-type mice fared better than transgenic mice. Transgenic mice showed higher serum levels of a marker for liver injury and greater evidence of damage in tissue examined microscopically.
Bcl-xL's broader potential for protecting the liver became apparent in experiments that measured the effect of TNF-alpha, an immune-system substance that plays a role in development of a wide variety of liver disorders. TNF-alpha induced severe liver damage in the transgenic, Bcl-xL-impaired mice but not in the wild-type mice.
"The human Bcl-xL protein is functionally identical to the mouse protein, so the same effects are expected in humans," Weintraub says. "If you took a population of people, you would likely see variation in Bcl-xL levels from person to person. In addition, Bcl-xL levels in each person are altered at times in response to certain stimuli. Therefore, it's possible that because of variation in Bcl-xL levels some individuals are more prone to develop tumors or more susceptible to tissue injury during their lifetimes. And at various times in each person's life, changing levels of Bcl-xL may increase the risk of either tumor development or tissue injury." According to Weintraub, a good example of the interplay between the two roles of Bcl-xL is seen in Barrett's esophagus, a precancerous change in the esophagus in response to chronic gastric reflux. Bcl-xL levels go up in areas exposed to stomach acid, presumably to protect the esophageal tissue from damage. Unfortunately, the risk of esophageal cancer increases 30 to 60 times in patients with this condition. "On the positive side, our findings suggest the possibility of preventing tissue injury by specifically increasing levels of Bcl-xL during disease treatments that adversely affect particular organs," Weintraub says.
Henderson CC, Zhang Z, Manson SR, Riehm JJ, Kataoka M, Flye MW, Garbow JR, You M, Weintraub SJ. A moderate reduction of Bcl-XL expression protects against tumorigenesis; however, it also increases susceptibility to tissue injury. Oncogene, advance online publication July 11, 2005.
Funding from the National Institutes of Health, the Washington University Digestive Diseases Research Core Center, the Elsa U Pardee Foundation, the Midwest Stone Institute, and the Goldman Philanthropic Partnerships Culpeper Biomedical Pilot Initiative supported this research.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
By Gwen Ericson
Journal
Oncogene