The Role of Chk2 in Areca Nuts-Induced Cytotoxicity
Date Issued
2009
Date
2009
Author(s)
Wang, Wei-Ting
Abstract
Betel quid (BQ) chewing is a very common habit in Asia, Africa, and a portion of Europe. It enjoys complete social acceptance in many societies especially in Thailand, Malaysia, Indonesia, India, China and Taiwan. It has been estimated that there are about 6 million BQ-chewers living in different regions of the world. BQ chewing is demonstrated to be one of the major risk factors leading to leukoplakia, oral submucous fibrosis, and oral cancer. In a monograph published by the International Agency for Research on Cancer（IARC）for the evaluation of cancer risks (IARC, 2004), areca nut was ranked as a group I carcinogen to humans. There are many reports indicating the components of areca nuts have genotoxicity and cytotoxicity leading to DNA strands breaks, DNA-proteins crosslink, unschedualed DNA synthesis and cell cycle aberration. When DNA damage occurs, the ATM/ATR-Chk1/Chk2 pathway is activated, cell cycle arrested, and induces the activation of other DNA-repair proteins. So far, because of the components of AN are very complex, the mechanisms of AN-induced cytotoxicity to cause cell aberrations and oral diseases are not clearly understood. The purpose of this study is trying to investigate the roles of two check point kineses: Chk1/Chk2 in the ANE-induced geno- and cytotoxicity. In the ANE-dose dependent experiments, the morphology of SAS cells became much roundly, lost the connection to the plate and many vacuoles appeared in the cells due to the increased ANE-concentration. The viability of SAS cells decreased obviously because of the raised of the ANE and arecoline, especially in the concentration of 800 ug/ml and 0.8 mM respectively. By using flow-cytometry assay, we found that the SAS cells arrested in G2/M phase because of the effects of the components of areca nuts. We further analysed whether the ANE and the arecoline can regulate the cell cycle- and apoptosis-related molecules by RT-PCR and western blot. ANE and arecoline activated the Chk2 pathway and induced the downstream p-Cdc2, p-Cdc25C expression through the Chk2 phosphorylation. The ANE and arecoline also regulated the cell cycle-related cyclin B1, cyclin D1 and the apoptosis-related p-p53, Bax and bcl-2. By using caffeine, an ATM/ATR inhibitor and Chk2 inhibitor, we clarified the correlation between the molecules of the ATM-Chk2 signaling transduction pathway. Unexpectedly, Chk2 inhibition not only blocked the ANE-induced G2/M phase arrest of SAS cells but also resulted in the G1 phase arrest. In conclusion, we provide the possible molecular mechanism of Chk2 pathway, which is induced by ANE and arecoline to cause aberration in SAS cells. Chk2 activation indeed plays a very important role in the cell mutagenesis induced by areca nuts components. Maybe Chk2 can be the new target in the prevention and clinical treatment of the areca nuts-induced oral mucosa diseases in the future.
Subjects
ANE
arecoline
cytotoxicity
cell cycle
SDGs
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