title: Areca nut components stimulate ADAM17, IL-1α, PGE2 and 8-isoprostane production in oral keratinocyte: role of reactive oxygen species, EGF and JAK signaling.
abstract: Betel quid (BQ) chewing is an etiologic factor of oral submucous fibrosis (OSF) and oral cancer. There are 600 million BQ chewers worldwide. The mechanisms for the toxic and inflammatory responses of BQ are unclear. In this study, both areca nut (AN) extract (ANE) and arecoline stimulated epidermal growth factor (EGF) and interleukin-1α (IL-1α) production of gingival keratinocytes (GKs), whereas only ANE can stimulate a disintegrin and metalloproteinase 17 (ADAM17), prostaglandin E2 (PGE2) and 8-isoprostane production. ANE-induced EGF production was inhibited by catalase. Addition of anti-EGF neutralizing antibody attenuated ANE-induced cyclooxygenase-2 (COX-2), mature ADAM9 expression and PGE2 and 8-isoprostane production. ANE-induced IL-1α production was inhibited by catalase, anti-EGF antibody, PD153035 (EGF receptor antagonist) and U0126 (MEK inhibitor) but not by α-naphthoflavone (cytochrome p450-1A1 inhibitor). ANE-induced ADAM17 production was inhibited by pp2 (Src inhibitor), U0126, α-naphthoflavone and aspirin. AG490 (JAK inhibitor) prevented ANE-stimulated ADAM17, IL-1α, PGE2 production, COX-2 expression, ADAM9 maturation, and the ANE-induced decline in keratin 5 and 14, but showed little effect on cdc2 expression and EGF production. Moreover, ANE-induced 8-isoprostane production by GKs was inhibited by catalase, anti-EGF antibody, AG490, pp2, U0126, α-naphthoflavone, Zinc protoporphyrin (ZnPP) and aspirin. These results indicate that AN components may involve in BQ-induced oral cancer by induction of reactive oxygen species, EGF/EGFR, IL-1α, ADAMs, JAK, Src, MEK/ERK, CYP1A1, and COX signaling pathways, and the aberration of cell cycle and differentiation. Various blockers against ROS, EGF, IL-1α, ADAM, JAK, Src, MEK, CYP1A1, and COX can be used for prevention or treatment of BQ chewing-related diseases.
authors.affiliation: Team of Biomedical Science, Chang-Gung University of Science and Technology, Kwei-Shan, Taoyuan City, Taiwan.|Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan.
authors.forename: Mei-Chi
authors.initials: MC
authors.lastname: Chang
authors.affiliation: Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan.
authors.forename: Chiu-Po
authors.initials: CP
authors.lastname: Chan
authors.affiliation: Laboratory of Pharmacology, Toxicology and Chemical Carcinogenesis, School of Dentistry and Department of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan.
authors.forename: Yi-Jane
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan.
authors.forename: Hsiang-Chi
authors.initials: HC
authors.lastname: Hsien
authors.affiliation: Department of Dentistry, Mackay Memorial Hospial, and Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan.
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan.
authors.forename: Sin-Yuet
authors.initials: SY
authors.lastname: Yeung
authors.affiliation: School of Dentistry, University of Cardenal Herrera, CEU, Valencia, Spain.
authors.forename: Po-Yuan
authors.initials: PY
authors.lastname: Jeng
authors.affiliation: Laboratory of Pharmacology, Toxicology and Chemical Carcinogenesis, School of Dentistry and Department of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan.
authors.forename: Ru-Hsiu
authors.initials: RH
authors.lastname: Cheng
authors.affiliation: Laboratory of Pharmacology, Toxicology and Chemical Carcinogenesis, School of Dentistry and Department of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan.
authors.forename: Liang-Jiunn
authors.initials: LJ
authors.lastname: Hahn
authors.affiliation: Laboratory of Pharmacology, Toxicology and Chemical Carcinogenesis, School of Dentistry and Department of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan.
authors.forename: Jiiang-Huei
authors.initials: JH
authors.lastname: Jeng
mesh_terms: D000072198:ADAM17 Protein / Q000187:drug effects / Q000378:metabolism; D001114:Areca / Q000633:toxicity*; D002460:Cell Line; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000187:drug effects / Q000378:metabolism; D005881:Gingiva / Q000187:drug effects*; D006801:Humans; D053582:Interleukin-1alpha / Q000378:metabolism; D053612:Janus Kinases / Q000187:drug effects / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects*; D010936:Plant Extracts / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C508584:IL1A protein, human; D053582:Interleukin-1alpha; D010936:Plant Extracts; D017382:Reactive Oxygen Species; C075750:8-epi-prostaglandin F2alpha; D004815:Epidermal Growth Factor; D015237:Dinoprost; D053612:Janus Kinases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; D015232:Dinoprostone
keywords: betel quid; epidermal growth factor; oral cancer; prostanoids; signal transduction