title: Oestrogen and progesterone increase the levels of apoptosis induced by the human papillomavirus type 16 E2 and E7 proteins.
abstract: Human papillomavirus (HPV) type 16 infects the genital tract and is generally acknowledged to be a causative agent of cervical cancer. HPV infection alone is not sufficient to induce cervical cancer and other factors such as steroid hormones are thought to play a role in the establishment and/or progression of this disease. The HPV-16 E2 protein is required for virus replication and modulates viral gene expression whereas the HPV-16 E7 protein is required for cell transformation. We and others have shown that both the E2 and E7 proteins can induce apoptotic cell death in HPV-transformed and non-HPV transformed cell lines. Here we show that the steroid hormones oestrogen and progesterone can both increase the levels of E2- and E7-induced apoptosis. The oestrogen metabolite 16 alpha-hydroxyoestrone also increases E2- and E7-induced cell death and the dietary component indole-3-carbinol, which reduces the formation of 16alpha-hydroxyoestrone from oestrogen, blocks the effects of oestrogen. Thus the metabolism of oestrogen to 16 alpha-hydroxyoestrone appears to be required for the effects of this hormone on E2- and E7-induced cell death. We also show that the oestrogen receptor antagonist 3-hydroxytamoxifen blocks the effects of oestrogen on E2- and E7-induced cell death, whereas the anti-progesterone RU486 blocks the effects of both progesterone and oestrogen. We discuss these results in terms of the origin and progression of cervical cancer.
authors: Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK1.
authors: Kenneth
authors: K
authors: Webster
authors: Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK1.
authors: Anna
authors: A
authors: Taylor
authors: Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK1.
authors: Kevin
authors: K
authors: Gaston
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D006894:Hydroxyestrones / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D009856:Oncogene Proteins, Viral / Q000494:pharmacology*; D027383:Papillomaviridae / Q000737:chemistry*; D050725:Papillomavirus E7 Proteins; D011374:Progesterone / Q000819:agonists / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000819:agonists; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; D004967:Estrogens; D006894:Hydroxyestrones; D007211:Indoles; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011960:Receptors, Estrogen; C059731:oncogene protein E7, Human papillomavirus type 16; D013629:Tamoxifen; C038345:droloxifene; D015735:Mifepristone; D011374:Progesterone; C016517:indole-3-carbinol