title: Screening of drugs to counteract human papillomavirus 16 E6 repression of E-cadherin expression.
abstract: Persistent infections with certain high-risk human papillomavirus (HPV) types such as 16 and 18 can result in the development of cervical cancer. Neither of the two prophylactic vaccines against HPV16 and 18 that are in current use have any therapeutic efficacy for prevalent HPV infections. Ablative therapy is widely used for the treatment of HPV cervical dysplasia however disease recurrence is a widely recognized problem. Thus there is a continuing need for therapeutic approaches for the treatment of HPV infections. The HPV16 E6 viral oncoprotein represses surface expression of the cellular adhesion molecule, E-cadherin. Reduced E-cadherin expression on HPV-infected keratinocytes is associated with lowered numbers of antigen-presenting Langerhans cells in the infected epidermis, potentially reducing immune surveillance for HPV. Four chemicals reported to up-regulate E-cadherin were screened for their ability to counteract E6 repression of surface E-cadherin. 5-Aza-2'-deoxycytidine (AzaDC), a DNA methyltransferase inhibitor, and Indole-3-carbinol (I3C), reported to increase E-cadherin through a p21(Waf1/Cip1)-dependent mechanism, had low cytotoxicity and increased or restored E-cadherin expression and adhesive function in HPV16 E6 expressing HCT116 cells. Doxorubicin, also known to induce p21(Waf1/Cip1), increased E-cadherin in E6 expressing cells but had some associated cytotoxicity. Tamoxifen, which can restore adhesive function of surface E-cadherin, was ineffective in counteracting E6 repression of E-cadherin. AzaDC and I3C both show potential to restore antigen-presenting cells to HPV infected skin by antagonizing E6 repression of E-cadherin, thereby counteracting an important immune evasion mechanism of HPV16 and reinstating immune function at the infected site.
authors.affiliation: Department of Microbiology and Immunology, University of Otago, P.O. Box 56, Dunedin, 9054, New Zealand.
authors.forename: Zarina J
authors.initials: ZJ
authors.lastname: D'Costa
authors.forename: Cheng-Mee
authors.initials: CM
authors.lastname: Leong
authors.forename: Justin
authors.initials: J
authors.lastname: Shields
authors.forename: Charles
authors.initials: C
authors.lastname: Matthews
authors.forename: Merilyn H
authors.initials: MH
authors.lastname: Hibma
mesh_terms: D000998:Antiviral Agents; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004317:Doxorubicin / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D015820:Cadherins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C068651:E6 protein, Human papillomavirus type 16; D007211:Indoles; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D013629:Tamoxifen; D000077209:Decitabine; D004317:Doxorubicin; C016517:indole-3-carbinol; D001374:Azacitidine