Jan. 28, 2005 PHILADELPHIA -- Tobacco smoke triggers the production of COX-2, a cellular protein linked to the development and progression of cancer, according to research published in the January 15 issue of the journal Cancer Research.
Tobacco smoke also promoted rapid cellular production of two proteins that initiate an epidermal growth factor receptor (EGFR) driven cascade leading to the production of COX-2, the report stated.
The report by Andrew J. Dannenberg, M.D., director of cancer prevention, Weill Medical College of Cornell University, and colleagues, indicates that smokers produce as much as four times the amount of COX-2 in oral mucosal cells lining their mouths than their non-smoking counterparts.
After observing the increased amount of COX-2 in the oral mucosa of smokers, Dannenberg and his team of collaborating scientists exposed cells in culture to tobacco smoke to define the mechanism underlying smoke-induced elevation of COX-2.
The researchers determined that COX-2 levels were increased due to tobacco smoke induced activation of EGFR, a cell membrane protein also associated with various types of cancer. Tobacco smoke stimulated the oral mucosal cells to rapidly release two proteins that activate the EGFR, initiating a cascade resulting in COX-2 protein production.
"In an oral mucosal cell line, tobacco smoke clearly activated the epidermal growth factor receptor. Tobacco smoke caused increased EGFR phosphorylation leading to increased COX-2 production," Dannenberg reported.
"We were able to block the induction of COX-2 with either a small molecule that inhibited EGFR activity or an antibody that prevented ligands from binding to and activating the EGFR. These findings led us to question whether tobacco smoke initiated the process of increasing COX-2 production by first stimulating production of proteins that controlled activity of the EGF receptor," Dannenberg said.
Cells exposed to tobacco smoke increased production of two EGFR ligands, or proteins that bind to and activate the growth factor receptor. Tobacco smoke exposed oral mucosal cells produced more amphiregulin and TGF-alpha, both of which trigger EGFR function.
"Cellular release of both of these EGFR ligands occurred quickly after exposure to tobacco smoke," Dannenberg said. These findings appear to be directly relevant to people because increased levels of both proteins were also detected in oral biopsies from smokers.
"These results provide new insights into the mechanism by which tobacco smoke causes cancer. Mutations can only occur in proliferating cells and activation of EGFR signaling enhances cell proliferation," Dannenberg said.
"These results strengthen the rational for targeting not only COX-2, but also EGFR as approaches for reducing the risk of tobacco-related malignancies of the mouth and throat," Dannenberg said.
Dannenberg investigated the mechanism of tobacco smoke effects on oral mucosa with team of scientists including Dimitrios Moraitis, M.D., Jay O. Boyle, M.D., and Erik G. Cohen, M.D., Memorial Sloan-Kettering Cancer Center, New York, N.Y; Baoheng Du, M.D., Mariana S. De Lorenzo, Ph.D., Babette B. Weksler, M.D., Kotha Subbaramaiah, Ph.D., John F. Carew, M.D., and Nasser K. Altorki, M.D., Weil Medical College of Cornell University, New York, N.Y.; and Levy Kopelovich, Ph.D., National Cancer Institute, Bethesda, M.D.
Founded in 1907, the American Association for Cancer Research is a professional society of more than 24,000 laboratory, translational, and clinical scientists engaged in all areas of cancer research in the United States and in more than 60 other countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication, and advocacy. Its principal activities include the publication of five major peer-reviewed scientific journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. AACR's Annual Meetings attract more than 15,000 participants who share new and significant discoveries in the cancer field. Specialty meetings, held throughout the year, focus on the latest developments in all areas of cancer research.
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