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Histopathologically<jats:styled-content style=\"fixed-case\">OSF<\/jats:styled-content>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 (<jats:styled-content style=\"fixed-case\">ANW<\/jats:styled-content>) was cytotoxic to epithelial cells and had a pro\u2010proliferative effect on fibroblasts. This opposite effect of<jats:styled-content style=\"fixed-case\">ANW<\/jats:styled-content>on epithelial and fibroblast cells was intriguing but reflects the<jats:styled-content style=\"fixed-case\">OSF<\/jats:styled-content>histopathology such as epithelial atrophy and proliferation of fibroblasts. We demonstrate that the pro\u2010proliferative effects of<jats:styled-content style=\"fixed-case\">ANW<\/jats:styled-content>on fibroblasts are dependent on insulin\u2010like 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<jats:styled-content style=\"fixed-case\">ANW<\/jats:styled-content>along with copper resulted in enhanced cytotoxicity which becomes comparable to<jats:styled-content style=\"fixed-case\">IC<\/jats:styled-content><jats:sub>50<\/jats:sub>of<jats:styled-content style=\"fixed-case\">ANW<\/jats:styled-content>. 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<jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content>which could generate an apoptotic response. Terminal deoxynucleotidyl transferase dUTP Nick End Labeling assay and Ki\u201067 index of<jats:styled-content style=\"fixed-case\">OSF<\/jats:styled-content>tissue sections suggested epithelial apoptosis, which could be responsible for the atrophy of<jats:styled-content style=\"fixed-case\">OSF<\/jats:styled-content>epithelium.<\/jats:p>","DOI":"10.1111\/jcmm.12622","type":"journal-article","created":{"date-parts":[[2015,8,7]],"date-time":"2015-08-07T03:57:02Z","timestamp":1438919822000},"page":"2397-2412","source":"Crossref","is-referenced-by-count":50,"title":["Epithelial atrophy in oral submucous fibrosis is mediated by copper (II) and arecoline of areca nut"],"prefix":"10.1111","volume":"19","author":[{"given":"Imran","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Molecular Reproduction, Development and Genetics Indian Institute of Science Bangalore India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ila","family":"Pant","sequence":"additional","affiliation":[{"name":"Department of Molecular Reproduction, Development and Genetics Indian Institute of Science Bangalore India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sivakrishna","family":"Narra","sequence":"additional","affiliation":[{"name":"Department of Molecular Reproduction, Development and Genetics Indian Institute of Science Bangalore India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rekha","family":"Radhesh","sequence":"additional","affiliation":[{"name":"Clumax Diagnostics Bangalore India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kannan","family":"Ranganathan","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology Ragas Dental College and Hospital Chennai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somanahalli Girish","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery D.A. Pandu Memorial \u2010 R.V. Dental College and Hospital Bangalore India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paturu","family":"Kondaiah","sequence":"additional","affiliation":[{"name":"Department of Molecular Reproduction, Development and Genetics Indian Institute of Science Bangalore India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,8,6]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"985","article-title":"Oral submucous fibrosis: etiology, pathogenesis, and future research","volume":"72","author":"Rajendran R","year":"1994","journal-title":"Bull World Health Organ"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0714.2007.00523.x"},{"key":"e_1_2_7_4_1","first-page":"5294","article-title":"Cytotoxic and genotoxic effects of areca nut\u2010related compounds in cultured human buccal epithelial cells","volume":"49","author":"Sundqvist K","year":"1989","journal-title":"Cancer Res"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0765.2008.01176.x"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0714.1994.tb01103.x"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0051806"},{"key":"e_1_2_7_8_1","first-page":"247","article-title":"Estimation and comparison of copper content in raw areca nuts and commercial areca nut products: implications in increasing prevalence of oral submucous fibrosis (OSMF)","volume":"8","author":"Mathew P","year":"2014","journal-title":"J Clin Diagn Res"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(97)24020-1"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0714.2000.290601.x"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/6.2.295"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.3109\/08977194.2011.582839"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.106.3.761"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(92)90008-H"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)50881-X"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.88.2281.263"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0074-7696(08)62312-8"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.182.5.1545"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.119.3.493"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1177\/00220345940730050501"},{"key":"e_1_2_7_21_1","first-page":"1","article-title":"Betel\u2010quid and areca\u2010nut chewing and some areca\u2010nut derived nitrosamines","volume":"85","author":"IARC","year":"2004","journal-title":"IARC Monogr Eval Carcinog Risks Hum"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinorgbio.2012.06.006"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4652(199701)170:1<69::AID-JCP8>3.0.CO;2-J"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2005.05.006"},{"key":"e_1_2_7_25_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0022-3565(24)29655-5","article-title":"Cellular thiols and reactive oxygen species in drug\u2010induced apoptosis","volume":"296","author":"Davis W","year":"2001","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2012.02294.x"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.010909.105600"},{"key":"e_1_2_7_28_1","doi-asserted-by":"crossref","first-page":"25557","DOI":"10.1016\/S0021-9258(18)47285-7","article-title":"Zinc(II) and copper(II) binding to serum albumin. 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