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Receptor-mediated tobacco toxicity: cooperation of the Ras/Raf-1/MEK1/ERK and JAK-2/STAT-3 pathways downstream of 7 nicotinic receptor in oral keratinocytes

Juan Arredondo^*, Alexander I. Chernyavsky^*, David L. Jolkovsky, Kent E. Pinkerton and Sergei A. Grando^*,1

^* Department of Dermatology and

Center for Health and the Environment, University of California, Davis; and

Section of Periodontics, School of Dentistry, University of California, Los Angeles, California, USA

¹Correspondence: Department of Dermatology, University of California Davis Medical Center, 3301 C St., Ste. 1400, Sacramento, CA 95816, USA. E-mail: sagrando{at}ucdavis.edu

The use of tobacco products is associated with an increased incidence of periodontal disease, poor response to periodontal therapy, and a high risk for developing head and neck cancer. Nicotine and tobacco-derived nitrosamines have been shown to exhibit their pathobiologic effects due in part to activation of the nicotinic acetylcholine (ACh) receptors (nAChRs), mainly 7 nAChR, expressed by oral keratinocytes (KCs). This study was designed to gain mechanistic insight into 7-mediated morbidity of tobacco products in the oral cavity. We investigated the signaling pathways downstream of 7 nAChR in monolayers of oral KCs exposed for 24 h to aged and diluted sidestream cigarette smoke (ADSS) or an equivalent concentration of pure nicotine. By both real-time polymerase chain reaction (PCR) and In-cell Western, the KCs stimulated with ADSS or nicotine showed multifold increases of STAT-3. These effects could be completely blocked or significantly (P<0.05) diminished if the cells were pretreated with the 7 antagonist -bungarotoxin (BTX) or transfected with anti-7 small interfering RNA (siRNA-7). The use of pathway inhibitors revealed that signaling through the Ras/Raf-1/MEK1/ERK steps mediated 7-dependent up-regulation of STAT-3. Targeted mutation of the 7 gene prevented ERK1/2 activation by nicotine. Using the gel mobility shift assay, we demonstrated that an increased protein binding activity of STAT-3 caused by ADSS or pure nicotine was mediated by janus-activated kinase (JAK)-2. Activation of JAK-2/STAT-3 pathway could be prevented by BTX or siRNA-7. Thus, nuclear transactivation of STAT-3 in KCs exposed to tobacco products is mediated via intracellular signaling downstream from 7, which proceeds via two complementary pathways. The Ras/Raf-1/MEK1/ERK cascade culminates in up-regulated expression of the gene encoding STAT-3, whereas recruitment and activation of tyrosine kinase JAK-2 phosphorylates it. Elucidation of this novel mechanism of nicotine-dependent nuclear transactivation of STAT-3 identifies oral 7 nAChR as a promising molecular target to prevent, reverse, or retard tobacco-related periodontal disease and progression of head and neck cancer by receptor inhibitors.—Arredondo, J., Chernyavsky, A. I., Jolkovsky, D. L., Pinkerton, K. E., Grando, S. A. Receptor-mediated tobacco toxicity: cooperation of the Ras/Raf-1/MEK1/ERK and JAK-2/STAT-3 pathways downstream of 7 nicotinic receptor in oral keratinocytes.

Key Words: nicotinic ACh receptors • gene expression • oral cancer • periodontal therapy

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