Chang M.-C.Chan C.-P.YI-JANE CHENHsien H.-C.Chang Y.-C.Yeung S.-Y.Jeng P.-Y.Cheng R.-H.Hahn L.-J.JIIANG-HUEI JENG2021-07-082021-07-0820161949-2553https://www.scopus.com/inward/record.uri?eid=2-s2.0-84971612046&doi=10.18632%2foncotarget.7621&partnerID=40&md5=a0811a29c680824e2bfeb1170c86294bhttps://scholars.lib.ntu.edu.tw/handle/123456789/570643Betel 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.[SDGs]SDG31,4 diamino 1,4 bis(2 aminophenylthio) 2,3 dicyanobutadiene; 4 (3 bromoanilino) 6,7 dimethoxyquinazoline; 8 isoprostane; acetylsalicylic acid; ADAM protein; ADAM17 protein; ADAM9 protein; alpha naphthoflavone; areca nut extract; arecoline; catalase; cyclin dependent kinase 1; cyclooxygenase 2; cytochrome P450 1A1; cytokeratin 14; cytokeratin 5; disintegrin; epidermal growth factor; epidermal growth factor receptor; interleukin 1alpha; Janus kinase; metalloproteinase; metalloproteinase 17; n benzyl 2 cyano 3 (3,4 dihydroxyphenyl)acrylamide; plant extract; prostaglandin E2; protoporphyrin zinc; reactive oxygen metabolite; unclassified drug; 8-epi-prostaglandin F2alpha; ADAM17 protein, human; epidermal growth factor; IL1A protein, human; interleukin 1alpha; Janus kinase; plant extract; prostaglandin E2; prostaglandin F2 alpha; reactive oxygen metabolite; tumor necrosis factor alpha converting enzyme; Article; cell cycle; cell differentiation; controlled study; cytokine production; drug mechanism; enzyme activity; human; human cell; keratinocyte; mouth cancer; prostaglandin synthesis; protein expression; protein function; signal transduction; analogs and derivatives; Areca; cell line; drug effects; gingiva; keratinocyte; metabolism; signal transduction; toxicity; ADAM17 Protein; Areca; Cell Line; Dinoprost; Dinoprostone; Epidermal Growth Factor; Gingiva; Humans; Interleukin-1alpha; Janus Kinases; Keratinocytes; Plant Extracts; Reactive Oxygen Species; Signal Transductionjournal article10.18632/oncotarget.7621269192422-s2.0-84971612046