Epithelial atrophy in oral submucous fibrosis is mediated by copper (II) and arecoline of areca nut

Khan, Imran and Pant, Ila and Narra, Sivakrishna and Radhesh, Rekha and Ranganathan, Kannan and Rao, Somanahalli Girish and Kondaiah, Paturu (2015) Epithelial atrophy in oral submucous fibrosis is mediated by copper (II) and arecoline of areca nut. In: JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 19 (10). pp. 2397-2412.

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Abstract

Exposure of oral cavity to areca nut is associated with several pathological conditions including oral submucous fibrosis (OSF). Histopathologically OSF is characterized by epithelial atrophy, chronic inflammation, juxtaepithelial hyalinization, leading to fibrosis of submucosal tissue and affects 0.5% of the population in the Indian subcontinent. As the molecular mechanisms leading to atrophied epithelium and fibrosis are poorly understood, we studied areca nut actions on human keratinocyte and gingival fibroblast cells. Areca nut water extract (ANW) was cytotoxic to epithelial cells and had a pro-proliferative effect on fibroblasts. This opposite effect of ANW on epithelial and fibroblast cells was intriguing but reflects the OSF histopathology such as epithelial atrophy and proliferation of fibroblasts. We demonstrate that the pro-proliferative effects of ANW on fibroblasts are dependent on insulin-like growth factor signalling while the cytotoxic effects on keratinocytes are dependent on the generation of reactive oxygen species. Treatment of keratinocytes with arecoline which is a component of ANW along with copper resulted in enhanced cytotoxicity which becomes comparable to IC50 of ANW. Furthermore, studies using cyclic voltammetry, mass spectrometry and plasmid cleavage assay suggested that the presence of arecoline increases oxidation reduction potential of copper leading to enhanced cleavage of DNA which could generate an apoptotic response. Terminal deoxynucleotidyl transferase dUTP Nick End Labeling assay and Ki-67 index of OSF tissue sections suggested epithelial apoptosis, which could be responsible for the atrophy of OSF epithelium.

Item Type:	Journal Article
Publication:	JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Publisher:	WILEY-BLACKWELL
Additional Information:	Copy right for this article belongs to the WILEY-BLACKWELL, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
Keywords:	areca nut cytotoxicity; copper; epithelial atrophy
Department/Centre:	Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Date Deposited:	30 Oct 2015 07:02
Last Modified:	30 Oct 2015 07:02
URI:	http://eprints.iisc.ac.in/id/eprint/52638

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