Journal Article

Arecoline downregulates levels of p21 and p27 through the reactive oxygen species/mTOR complex 1 pathway and may contribute to oral squamous cell carcinoma

Yang, Sheng‐Ru, Cheng, Ya‐Ping, Ji, Wen‐Tsai, Chiang, Ming‐Ko, Chen, Hau‐Ren, Lee, Ying‐Ray, Chen, Jeff Yi‐Fu

2012

Overview

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. (Cancer Sci 2012; 103: 1221–1229)

• Publisher: John Wiley and Sons Inc
• Subject: Alkaloids / Arecoline - pharmacology / Blotting, Western / Carcinogenesis / Carcinogens / Carcinoma, Squamous Cell - genetics / Carcinoma, Squamous Cell - metabolism / Carcinoma, Squamous Cell - pathology / Cell cycle / Cell Line, Tumor / Cell Proliferation - drug effects / Cholinergic Agonists - pharmacology / Cyclin-Dependent Kinase Inhibitor p21 - genetics / Cyclin-Dependent Kinase Inhibitor p21 - metabolism / Cyclin-Dependent Kinase Inhibitor p27 - genetics / Cyclin-Dependent Kinase Inhibitor p27 - metabolism / Data processing / DNA biosynthesis / DNA Damage / Down-Regulation - drug effects / G1 Phase Cell Cycle Checkpoints - drug effects / G2 Phase Cell Cycle Checkpoints - drug effects / Genotoxicity / Humans / Male / Mechanistic Target of Rapamycin Complex 1 / Microscopy, Fluorescence / Mouth Neoplasms - genetics / Mouth Neoplasms - metabolism / Multiprotein Complexes - genetics / Multiprotein Complexes - metabolism / oral squamous cell carcinoma / Original / Reactive oxygen species / Reactive Oxygen Species - metabolism / Replication / Reverse Transcriptase Polymerase Chain Reaction / Signal Transduction - drug effects / TOR protein / TOR Serine-Threonine Kinases - genetics / TOR Serine-Threonine Kinases - metabolism / Tumor cell lines / Vacuoles