title: Arecoline downregulates levels of p21 and p27 through the reactive oxygen species/mTOR complex 1 pathway and may contribute to oral squamous cell carcinoma.
abstract: Arecoline, the major alkaloid of areca nut, has been shown to cause strong genotoxicity and is considered a potential carcinogen. However, the detailed mechanism for arecoline-induced carcinogenesis remains obscure. In this study, we noticed that the levels of p21 and p27 increased in two oral squamous cell carcinoma cell lines with high confluence. Furthermore, when treated with arecoline, elevated levels of p21 and p27 could be downregulated through the reactive oxygen species/mTOR complex 1 (ROS/mTORC1) pathway. Although arecoline decreased the activity of mTORC1, the amounts of autophagosome-like vacuoles or type II LC3 remained unchanged, suggesting that the downregulation of p21 and p27 was independent of autophagy-mediated protein destruction. Arecoline also caused DNA damage through ROS, indicating that the reduced levels of p21 and p27 might facilitate G (1) /S transition of the cell cycle and subsequently lead to error-prone DNA replication. In conclusion, these data have provided a possible mechanism for arecoline-induced carcinogenesis in subcytolytic doses in vivo.
authors.affiliation: Department of Life Science, Institute of Molecular Biology and Institute of Biomedical Science, College of Science, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan.
authors.forename: Wen-Tsai
authors.initials: WT
authors.lastname: Ji
authors.forename: Sheng-Ru
authors.initials: SR
authors.lastname: Yang
authors.forename: Jeff Yi-Fu
authors.initials: JY
authors.lastname: Chen
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Cheng
authors.forename: Ying-Ray
authors.initials: YR
authors.lastname: Lee
authors.forename: Ming-Ko
authors.initials: MK
authors.lastname: Chiang
authors.forename: Hau-Ren
authors.initials: HR
authors.lastname: Chen
mesh_terms: D001115:Arecoline / Q000494:pharmacology*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018679:Cholinergic Agonists / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D015536:Down-Regulation / Q000187:drug effects*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008856:Microscopy, Fluorescence; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018679:Cholinergic Agonists; D050759:Cyclin-Dependent Kinase Inhibitor p21; D046912:Multiprotein Complexes; D017382:Reactive Oxygen Species; D050760:Cyclin-Dependent Kinase Inhibitor p27; D001115:Arecoline; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases