Quadruple COX-2 in Smokers' Mouths

Smokers produce as much as four times the amount of COX-2 in oral mucosal cells lining their mouths than their non-smoking counterparts, write report authors Andrew J. Dannenberg, M.D., director of cancer prevention, Weill Medical College of Cornell University, and colleagues.

After observing the increased amount of COX-2 in the oral mucosa of smokers, Dr. 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.

They determined that COX-2 levels were increased due to tobacco smoke induced activation of EGFR (epidermal growth factor receptor), 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.

Smoke Triggers Chain Reaction

"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," Dr. 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 explained.

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.

Lab Study Directly Relevant to People

"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," Dr. Dannenberg said.

"These results strengthen the rationale 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.