Abstract
BackgroundApproximately 600 million people chew Betel nut, making this practice the fourth most popular oral habit in the world. Arecoline, the major alkaloid present in betel nut is one of the causative agents for precancerous lesions and several cancers of mouth among those who chew betel nut. Arecoline can be detected in the human embryonic tissue and is correlated to low birth weight of newborns whose mothers chew betel nut during pregnancy, suggesting that arecoline can induce many systemic effects. However, few reports exist as to the effects of arecoline in human tissues other than oral cancer cell lines. Furthermore, in any system, virtually nothing is known about the cellular effects of arecoline treatment on membrane associated signaling components of human cancer cells.ResultsUsing the human Ishikawa endometrial cancer cell line, we investigated the effects of arecoline on expression, localization and functional connections between the ZO-1 tight junction protein and the HER2 EGF receptor family member. Treatment of Ishikawa cells with arecoline coordinately down-regulated expression of both ZO-1 and HER2 protein and transcripts in a dose dependent manner. Biochemical fractionation of cells as well as indirect immunofluorescence revealed that arecoline disrupted the localization of ZO-1 to the junctional complex at the cell periphery. Compared to control transfected cells, ectopic expression of exogenous HER2 prevented the arecoline mediated down-regulation of ZO-1 expression and restored the localization of ZO-1 to the cell periphery. Furthermore, treatment with dexamethasone, a synthetic glucocorticoid reported to up-regulate expression of HER2 in Ishikawa cells, precluded arecoline from down-regulating ZO-1 expression and disrupting ZO-1 localization.ConclusionArecoline is known to induce precancerous lesions and cancer in the oral cavity of betel nut users. The arecoline down-regulation of ZO-1 expression and subcellular distribution suggests that arecoline potentially disrupts cell-cell interactions mediated by ZO-1, which may play a role in arecoline-mediated carcinogenesis. Furthermore, our study has uncovered the dependency of ZO-1 localization and expression on HER2 expression, which has therefore established a new cellular link between HER2 mediated signaling and apical junction formation involving ZO-1.
Highlights
600 million people chew Betel nut, making this practice the fourth most popular oral habit in the world
To examine the potential effects of arecoline on expression of the zonula occludens-1 (ZO-1) tight junction protein and HER2 member of the epidermal growth factor (EGF) receptor gene family, cultured human Ishikawas endometrial cancer cells were treated with concentrations of arecoline ranging between 0.1 mM and 0.5 mM and the production of ZO-1 and HER2 protein determined by western blot analysis
Arecoline induced cellular changes in the oral cavity in areca nut chewers leading to oral precancerous lesions may be due to disrupted expression and junctional localization of the ZO-1 tight junctional protein
Summary
600 million people chew Betel nut, making this practice the fourth most popular oral habit in the world. Arecoline can be detected in the human embryonic tissue and is correlated to low birth weight of newborns whose mothers chew betel nut during pregnancy, suggesting that arecoline can induce many systemic effects. Few reports exist as to the effects of arecoline in human tissues other than oral cancer cell lines. In any system, virtually nothing is known about the cellular effects of arecoline treatment on membrane associated signaling components of human cancer cells. Areca nut (Areca catechu Linn) chewing in the form of betel quid is popular in southeast Asian countries and plays a major role in the pathogenesis of precancerous lesions and several cancer of the oral cavity, including precancerous lesions such as leukoplakia and oral submucous fibrosis [1,2]. Exposure to arecoline has pleiotropic responses in a variety of tissue types that together account for its carcinogenic properties
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