Areca nut-induced buccal mucosa fibroblast contraction and its signaling: a potential role in oral submucous fibrosis--a precancer condition.
Betel quid (BQ) chewing is an oral habit that increases the risk of oral cancer and oral submucous fibrosis (OSF), a precancerous condition showing epithelial atrophy and tissue fibrosis. Persistent fibroblast contraction may induce the fibrotic contracture of tissue. In this study, we found that areca nut extract (ANE) (200-1200 µg/ml) stimulated buccal mucosa fibroblast (OMF)-populated collagen gel contraction. Arecoline but not arecaidine-two areca alkaloids, slightly induced the OMF contraction. Exogenous addition of carboxylesterase (2U/ml) prevented the arecoline- but not ANE-induced OMF contraction. OMF expressed inositol triphosphate (IP3) receptors. ANE-induced OMF (800 µg/ml) contraction was inhibited by U73122 [phospholipase C (PLC) inhibitor] and 2-aminoethoxydiphenyl borate (IP3 receptor antagonist), respectively. Ethylene glycol tetraacetic acid and verapamil, two calcium mobilization modulators, also suppressed the ANE-induced OMF contraction. ANE induced calcium/calmodulin kinase II and myosin light chain (MLC) phosphorylation in OMF. Moreover, W7 (a Ca(2+)/calmodulin inhibitor), HA1077 (Rho kinase inhibitor), ML-7 (MLC kinase inhibitor) and cytochalasin B (actin filament polymerization inhibitor) inhibited the ANE-induced OMF contraction. Although ANE elevated reactive oxygen species (ROS) level in OMF, catalase, superoxide dismutase and N-acetyl-L-cysteine showed no obvious effect on ANE-elicited OMF contraction. These results indicate that BQ chewing may affect the wound healing and fibrotic processes in OSF via inducing OMF contraction by ANE and areca alkaloids. AN components-induced OMF contraction was related to PLC/IP3/Ca(2+)/calmodulin and Rho signaling pathway as well as actin filament polymerization, but not solely due to ROS production.
Biomedical Science Team, Chang Gung University of Science and Technology, Kwei-Shan, Taoyuan, Taiwan.
Mei-Chi
MC
Chang
Li-Deh
LD
Lin
Hui-Lin
HL
Wu
Yuan-Soon
YS
Ho
Hsiang-Chi
HC
Hsien
Tong-Mei
TM
Wang
Po-Yuan
PY
Jeng
Ru-Hsiu
RH
Cheng
Liang-Jiunn
LJ
Hahn
Jiiang-Huei
JH
Jeng
D001114:Areca / Q000009:adverse effects*; D001115:Arecoline / Q000009:adverse effects / Q000031:analogs & derivatives; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D009061:Mouth Mucosa / Q000378:metabolism / Q000473:pathology*; D009062:Mouth Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D009754:Nuts / Q000009:adverse effects*; D009914:Oral Submucous Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000235:genetics; D010936:Plant Extracts / Q000009:adverse effects; D011230:Precancerous Conditions / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
D053496:Inositol 1,4,5-Trisphosphate Receptors; D018994:Myosin Light Chains; D010936:Plant Extracts; D017382:Reactive Oxygen Species; C015688:arecaidine; D001115:Arecoline; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium