Arecoline N‐oxide regulates oral squamous cell carcinoma development through NOTCH1 and FAT1 expressions

Areca nut has been evaluated as a group I carcinogen to humans. However, the exact compounds of areca nut causing oral cancer remain unproven. Previous findings from our lab revealed that arecoline N‐oxide (ANO), a metabolite of arecoline, exhibits an oral fibrotic effect in immune‐deficient NOD/SCID mice. The aim of this study is to investigate the oral potentially malignant disorders (OPMD) inductive activity between areca‐alkaloid arecoline and its metabolite ANO in C57BL/6 mice. Our findings show that ANO showed higher activity in inducing hyperplasia with leukoplakia and collagen deposition in C57BL/6 mice compared with the arecoline treated groups. Importantly, immunohistochemical studies showed significant upregulation of NOTCH1, HES1, FAT1, PCNA, and Ki67 expressions in the pathological hyperplastic part. In addition, in vitro studies showed that upregulation of NOTCH1 and FAT1 expressions in ANO treated HGF‐1 and DOK cell models. We found that NOTCH1 regulates TP53 expression from NOTCH1 knockdown oral cancer cells. The DNA damage was significantly increased after arecoline and ANO treatment. Further, we found that arecoline‐induced H2AX expression was regulated by FMO3. Altogether, our findings show that ANO exhibited higher toxicity in OPMD activity and play a significant role in the induction of areca nut mediated oral tumorigenesis.

• Publication year

  2019

• Venue

  Journal of Cellular Physiology

• Publication date

  2019-08-01

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.1002/jcp.28084PMID 30624777
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• FAT1 modulates EMT and stemness genes expression in hypoxic glioblastoma

  2018cited by this paper
• Interaction Between Rare Variants in NOTCH1 and Betel Quid Chewing in Oral Squamous Cell Carcinoma

  2017cited by this paper
• Arecoline N-Oxide Upregulates Caspase-8 Expression in Oral Hyperplastic Lesions of Mice.

  2017influential reference
• Integrative genomic and functional analysis of human oral squamous cell carcinoma cell lines reveals synergistic effects of FAT1 and CASP8 inactivation

  2016cited by this paper
• Somatic Mutations and Genetic Variants of NOTCH1 in Head and Neck Squamous Cell Carcinoma Occurrence and Development

  2016influential reference
• Molecular Pathology of Malignant Transformation of Oral Submucous Fibrosis.

  2016cited by this paper
• Proinflammatory cytokine levels in oral lichen planus, oral leukoplakia, and oral submucous fibrosis

  2015cited by this paper
• Activation of an endothelial Notch1-Jagged1 circuit induces VCAM1 expression, an effect amplified by interleukin-1β

  2015influential reference
• Notch is a direct negative regulator of the DNA-damage response

  2015cited by this paper
• Fibrotic Effects of Arecoline N-Oxide in Oral Potentially Malignant Disorders.

  2015influential reference
• Immunohistochemical detection of p53 and p63 in oral squamous cell carcinoma, oral leukoplakia, and oral submucous fibrosis.

  2014cited by this paper
• A synthetic lethal screen identifies FAT1 as an antagonist of caspase-8 in extrinsic apoptosis

  2014cited by this paper
• Betel-quid dependence domains and syndrome associated with betel-quid ingredients among chewers: an Asian multi-country evidence.

  2014cited by this paper
• Activation of the NOTCH pathway in head and neck cancer.

  2014cited by this paper
• Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers.

  2013influential reference
• Salivary levels of TNF-α and IL-6 in patients with oral premalignant and malignant lesions.

  2013cited by this paper
• Common and Complex Notch1 Mutations in Chinese Oral Squamous Cell Carcinoma

  2013cited by this paper
• A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins

  2013cited by this paper
• The pathological significance of Notch1 in oral squamous cell carcinoma

  2013influential reference
• Mutational landscape of gingivo-buccal oral squamous cell carcinoma reveals new recurrently-mutated genes and molecular subgroups

  2013cited by this paper
• Effects upon in-vivo nicotine metabolism reveal functional variation in FMO3 associated with cigarette consumption

  2013cited by this paper
• Betel-quid dependence and oral potentially malignant disorders in six Asian countries.

  2012cited by this paper
• Association of Betel Nut with Carcinogenesis: Revisit with a Clinical Perspective

  2012cited by this paper
• Population burden of betel quid abuse and its relation to oral premalignant disorders in South, Southeast, and East Asia: an Asian Betel-quid Consortium Study.

  2012cited by this paper
• iArc monogrAphs on the evAluAtion oF cArcinogenic risks to humAns

  2012cited by this paper
• The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

  2011influential reference
• Arecoline N-oxide: its mutagenicity and possible role as ultimate carcinogen in areca oral carcinogenesis.

  2011cited by this paper
• Human FAT1 cadherin controls cell migration and invasion of oral squamous cell carcinoma through the localization of β-catenin.

  2011cited by this paper
• NOTCH-1 and NOTCH-4 are novel gene targets of PEA3 in breast cancer: novel therapeutic implications

  2011cited by this paper
• Lymphocyte α-kinase is a gout-susceptible gene involved in monosodium urate monohydrate-induced inflammatory responses

  2011cited by this paper
• Exome Sequencing of Head and Neck Squamous Cell Carcinoma Reveals Inactivating Mutations in NOTCH1

  2011influential reference
• Human FAT1 cadherin controls cell migration and invasion of oral squamous cell carcinoma through the localization of β-catenin

  2011cited by this paper
• Salivary arecoline levels during areca nut chewing in human volunteers.

  2010cited by this paper
• Upregulation of Notch pathway molecules in oral squamous cell carcinoma.

  2010cited by this paper
• Co-treating with arecoline and 4-nitroquinoline 1-oxide to establish a mouse model mimicking oral tumorigenesis.

  2010cited by this paper
• Malignant transformation of oral potentially malignant disorders in males: a retrospective cohort study

  2009influential reference
• Cancer-promoting effect of Taiwan betel quid in hamster buccal pouch carcinogenesis.

  2008cited by this paper
• The metabolomics of (+/-)-arecoline 1-oxide in the mouse and its formation by human flavin-containing monooxygenases.

  2007cited by this paper
• Update on Oral Epithelial Dysplasia and Progression to Cancer

  2007cited by this paper
• A metabolomic approach to the metabolism of the areca nut alkaloids arecoline and arecaidine in the mouse.

  2006influential reference
• QUANTITATIVE ANALYSIS OF FMO GENE mRNA LEVELS IN HUMAN TISSUES

  2006cited by this paper
• Oral submucous fibrosis: review on aetiology and pathogenesis.

  2006cited by this paper
• Arecoline tumorigenicity in swiss strain mice on normal and vitamin B deficient diet

  2005cited by this paper
• Regulation of interleukin-6 expression by arecoline in human buccal mucosal fibroblasts is related to intracellular glutathione levels.

  2004cited by this paper
• Hamsters chewing betel quid or areca nut directly show a decrease in body weight and survival rates with concomitant epithelial hyperplasia of cheek pouch.

  2004cited by this paper
• The Induction of Prostaglandin E2 Production, Interleukin-6 Production, Cell Cycle Arrest, and Cytotoxicity in Primary Oral Keratinocytes and KB Cancer Cells by Areca Nut Ingredients Is Differentially Regulated by MEK/ERK Activation*

  2004cited by this paper
• Immune activation and chronic inflammation as the cause of malignancy in oral lichen planus: is there any evidence ?

  2004cited by this paper
• Betel-quid and areca-nut chewing and some areca-nut derived nitrosamines.

  2004cited by this paper
• Proliferative verrucous leukoplakia: high incidence of gingival squamous cell carcinoma.

  2003influential reference
• The precancer risk of betel quid chewing, tobacco use and alcohol consumption in oral leukoplakia and oral submucous fibrosis in southern Taiwan

  2003influential reference
• Global epidemiology of areca nut usage

  2002cited by this paper
• Role of areca nut in betel quid-associated chemical carcinogenesis: current awareness and future perspectives.

  2001cited by this paper
• Areca nut extract and arecoline induced the cell cycle arrest but not apoptosis of cultured oral KB epithelial cells: association of glutathione, reactive oxygen species and mitochondrial membrane potential.

  2001cited by this paper
• Proliferative verrucous leukoplakia and its related lesions.

  1999cited by this paper
• Studies on promoting activity of Taiwan betel quid ingredients in hamster buccal pouch carcinogenesis.

  1996cited by this paper
• Screening for oral cancer.

  1992cited by this paper
• Modifying influences of betel quid ingredients on B(a)P‐induced carcinogenesis in the buccal pouch of hamster

  1984influential reference
• Betel quid chewing and oral cancer: Experimental studies on hamsters

  1979cited by this paper
• Proliferative lesions in cheek pouch and esophagus of hamsters treated with plants from Curacao, Netherland Antilles.

  1974cited by this paper
• Carcinogenic Effect of a Dimethyl Sulphoxide Extract of Betel Nut on the Mucosa of the Hamster Buccal Pouch

  1971cited by this paper
• The effect of arecoline on the palatal and buccal mucosa of the Wistar rat. An optical and electron microscope study.

  1962cited by this paper
• The effect of arecoline on the palatal and buccal mucosa of the Wistar rat. An optical and electron microscope study.

  1962cited by this paper

• Drug Repurposing Targeting miRNA-mRNA Networks to Mitigate Areca Nut-Induced Head and Neck Cancer.

  2025cites this paper
• Role of Mutation of NOTCH1 gene in development of oral squamous cell carcinoma: a narrative review.

  2024cites this paper
• Diagnostic potential of salivary IL-1β, IL-8, SAT, S100P, and OAZ1 in oral squamous cell carcinoma, oral submucous fibrosis, and oral lichen planus based on findings from a Sri Lankan cohort

  2024cites this paper
• Sensitive Liquid Chromatography-Tandem Mass Spectrometry (LC–MS/MS) Analysis of Alkaloid Nitrogen Oxides at Three Different Processing Stages of Binglang

  2024cites this paper
• MYO1B as a prognostic biomarker and a therapeutic target in Arecoline‐associated oral carcinoma

  2023cites this paper
• Oxidative Stress and Endoplasmic Reticulum Stress Contributes to Arecoline and Its Secondary Metabolites-Induced Dyskinesia in Zebrafish Embryos

  2023cites this paper
• Systematic Review of Roles of Arecoline and Arecoline N-Oxide in Oral Cancer and Strategies to Block Carcinogenesis

  2023influential citation
• N-Oxides as Control Element for the Direction of a Sigmatropic Rearrangement. Application as a Switch for Fluorescence.

  2023cites this paper
• Evaluating Alterations of the Oral Microbiome and Its Link to Oral Cancer among Betel Quid Chewers: Prospecting Reversal through Probiotic Intervention

  2023cites this paper
• Exploring Possible Diagnostic Precancerous Biomarkers for Oral Submucous Fibrosis: A Narrative Review

  2023cites this paper
• Jiawei Danxuan Koukang Alleviates Arecoline Induced Oral Mucosal Lesions: Network Pharmacology and the Combined Ultra-High Performance Liquid Chromatography (UPLC) and Mass Spectrometry (MS)

  2023cites this paper
• A Critical Interpretive Synthesis of the Role of Arecoline in Oral Carcinogenesis: Is the Local Cholinergic Axis a Missing Link in Disease Pathophysiology?

  2023influential citation
• Mouse Models for Immune Checkpoint Blockade Therapeutic Research in Oral Cancer

  2022cites this paper
• Metabolism of the areca alkaloids – toxic and psychoactive constituents of the areca (betel) nut

  2022influential citation
• Arecoline N-oxide initiates oral carcinogenesis and arecoline N-oxide mercapturic acid attenuates the cancer risk.

  2021cites this paper
• Novel Pathways and Mechanism of Nicotine-Induced Oral Carcinogenesis.

  2021cites this paper
• Comprehensive Analysis of the Effects of Genetic Ancestry and Genetic Characteristics on the Clinical Evolution of Oral Squamous Cell Carcinoma

  2021cites this paper
• Genetic toxicology and toxicokinetics of arecoline and related areca nut compounds: an updated review

  2020cites this paper
• Identification of novel biomarkers and candidate small molecule drugs in rheumatoid arthritis and osteoarthritis based on bioinformatics analysis of high‐throughput data

  2020cites this paper
• Mouse Tumor-Bearing Models as Preclinical Study Platforms for Oral Squamous Cell Carcinoma

  2020cites this paper
• Betel quid-associated cancer: Prevention strategies and targeted treatment.

  2020cites this paper