1887

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 16α-hydroxyoestrone also increases E2- and E7-induced cell death and the dietary component indole-3-carbinol, which reduces the formation of 16α-hydroxyoestrone from oestrogen, blocks the effects of oestrogen. Thus the metabolism of oestrogen to 16α-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.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-82-1-201
2001-01-01
2020-01-28
Loading full text...

Full text loading...

/deliver/fulltext/jgv/82/1/0820201a.html?itemId=/content/journal/jgv/10.1099/0022-1317-82-1-201&mimeType=html&fmt=ahah

References

  1. Arbeit, J. M., Howley, P. M. & Hanahan, D. ( 1996; ). Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in human papillomavirus type 16 transgenic mice. Proceedings of the National Academy of Sciences, USA 93, 2930-2935.[CrossRef]
    [Google Scholar]
  2. Auborn, K. J., Woodworth, C., DiPaolo, J. A. & Bradlow, H. L. ( 1991; ). The interaction between HPV infection and estrogen metabolism in cervical carcinogenesis. International Journal of Cancer 49, 867-869.[CrossRef]
    [Google Scholar]
  3. Autier, P., Coibion, M., Huet, F. & Grivegnee, A. R. ( 1996; ). Transformation zone location and intraepithelial neoplasia of the cervix uteri. British Journal of Cancer 74, 488-490.[CrossRef]
    [Google Scholar]
  4. Baker, C. C., Phelps, W. C., Lindgren, V., Braun, M. J., Gonda, M. A. & Howley, P. M. ( 1987; ). Structural and transcriptional analysis of human papillomavirus type 16 sequences in cervical carcinoma cell lines. Journal of Virology 61, 962-971.
    [Google Scholar]
  5. Bhattacharya, D., Redkar, A., Mittra, I., Sutaria, U. & MacRae, K. D. ( 1997; ). Oestrogen increases S-phase fraction and oestrogen and progesterone receptors in human cervical cancer in vivo. British Journal of Cancer 75, 554-558.[CrossRef]
    [Google Scholar]
  6. Bosch, F. X., Manos, M. M., Munoz, N., Sherman, M., Jansen, A. M., Peto, J., Schiffman, M. H., Moreno, V., Kurman, R. & Shah, K. V. ( 1995; ). Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. Journal of the National Cancer Institute 87, 796-802.[CrossRef]
    [Google Scholar]
  7. Boyer, S. N., Wazer, D. E. & Band, V. ( 1996; ). E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitin–proteasome pathway. Cancer Research 56, 4620-4624.
    [Google Scholar]
  8. Brisson, J., Morin, C., Fortier, M., Roy, M., Bouchard, C., Leclerc, J., Christen, A., Guimont, C., Penault, F. & Meisels, A. ( 1994; ). Risk factors for cervical intraepithelial neoplasia: differences between low- and high-grade lesions. American Journal of Epidemiology 140, 700-710.
    [Google Scholar]
  9. Cadepond, F., Ulmann, A. & Baulieu, E.-E. ( 1997; ). RU486 (Mifepristone): mechanisms of action and clinical uses. Annual Review of Medicine 48, 129-156.[CrossRef]
    [Google Scholar]
  10. Chen, Y.-H., Huang, L.-H. & Chen, T.-M. ( 1996; ). Differential effects of progestins and estrogens on long control regions of human papillomavirus types 16 and 18. Biochemical and Biophysical Research Communications 224, 651-659.[CrossRef]
    [Google Scholar]
  11. Corden, S. A., Sant-Cassia, L. J., Easton, A. J. & Morris, A. G. ( 1999; ). The integration of HPV-18 DNA in cervical carcinoma. Molecular Pathology 52, 275-278.[CrossRef]
    [Google Scholar]
  12. Cover, C. M., Hsieh, S. J., Tran, S. H., Hallden, G., Kim, G. S., Bjeldanes, L. F. & Firestone, G. L. ( 1998; ). Indole-3-carbinol inhibits the expression of cyclin-dependent kinase-6 and induces a G1 cell cycle arrest of human breast cancer cells independent of estrogen receptor signaling. Journal of Biological Chemistry 273, 3838-3847.[CrossRef]
    [Google Scholar]
  13. Crook, T. & Vousden, K. H. (1996). In Papillomavirus Reviews: Current Research on Papillomaviruses, pp. 55–60. Edited by C. Lacey. Leeds: Leeds University Press.
  14. Desaintes, C., Demeret, C., Goyat, S., Yaniv, M. & Thierry, F. ( 1997; ). Expression of the papillomavirus E2 protein in HeLa cells leads to apoptosis. EMBO Journal 16, 504-514.[CrossRef]
    [Google Scholar]
  15. Dürst, M., Kleinheinz, A., Hotz, M. & Gissmann, L. ( 1985; ). The physical state of human papillomavirus type 16 DNA in benign and malignant genital tumours. Journal of General Virology 66, 1515-1522.[CrossRef]
    [Google Scholar]
  16. Dyson, N., Howley, P. M., Münger, K. & Harlow, E. ( 1989; ). The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243, 934-937.[CrossRef]
    [Google Scholar]
  17. Field, S. J., Tsai, F. Y., Kuo, F., Zubiaga, A. M., Kaelin, W. G.Jr, Livingston, D. M., Orkin, S. H. & Greenberg, M. E. ( 1996; ). E2F-1 functions in mice to promote apoptosis and suppress proliferation. Cell 85, 549-561.[CrossRef]
    [Google Scholar]
  18. Francis, D. A., Schmid, S. I. & Howley, P. M. ( 2000; ). Repression of the integrated papillomavirus E6/E7 promoter is required for growth suppression of cervical cancer cells. Journal of Virology 74, 2679-2686.[CrossRef]
    [Google Scholar]
  19. Frattini, M. G., Hurst, S. D., Lim, H. B., Swaminathan, S. & Laimins, L. A. ( 1997; ). Abrogation of a mitotic checkpoint by E2 proteins from oncogenic human papillomaviruses correlates with increased turnover of the p53 tumour suppressor protein. EMBO Journal 16, 318-331.[CrossRef]
    [Google Scholar]
  20. Groshong, S. D., Owen, G. I., Grimison, B., Schauer, I. E., Todd, M. C., Langan, T. A., Sclafani, R. A., Lange, C. A. & Horwitz, K. B. ( 1997; ). Biphasic regulation of breast cancer cell growth by progesterone: role of the cyclin-dependent kinase inhibitors, p21 and p27Kip1. Molecular Endocrinology 11, 1593-1607.[CrossRef]
    [Google Scholar]
  21. Hubbert, N. L., Sedman, S. A. & Schiller, J. T. ( 1992; ). Human papillomavirus type 16 E6 increases the degradation rate of p53 in human keratinocytes. Journal of Virology 66, 6237-6241.
    [Google Scholar]
  22. Hurd, C., Khattree, N., Alban, P., Nag, K., Jhanwar, S. C., Dinda, S. & Moudgil, V. K. ( 1995; ). Hormonal regulation of the p53 tumor suppressor protein in T47D human breast carcinoma cell line. Journal of Biological Chemistry 270, 28507-28510.[CrossRef]
    [Google Scholar]
  23. Jones, D. L., Thompson, D. A. & Münger, K. ( 1997; ). Destabilization of the RB tumor suppressor protein and stabilization of p53 contribute to HPV type 16 E7-induced apoptosis. Virology 239, 97-107.[CrossRef]
    [Google Scholar]
  24. Kamradt, M. C., Mohideen, N. & Vaughan, A. T. M. ( 1999; ). RU486 increases radiosensitivity and restores apoptosis through modulation of HPV E6/E7 in dexamethasone-treated cervical carcinoma cells. Gynecologic Oncology 77, 177-182.
    [Google Scholar]
  25. Kim, C. J., Um, S. J., Kim, T. Y., Kim, E. J., Park, T. C., Kim, S. J., Namkoong, S. E. & Park, J. S. ( 2000; ). Regulation of cell growth and HPV genes by exogenous estrogen in cervical cancer cells. International Journal of Gynecology & Obstetrics 10, 157–164.
    [Google Scholar]
  26. Lechner, M. S., Mack, D. H., Finicle, A. B., Crook, T., Vousden, K. H. & Laimins, L. A. ( 1992; ). Human papillomavirus E6 proteins bind p53 in vivo and abrogate p53-mediated repression of transcription. EMBO Journal 11, 3045-3052.
    [Google Scholar]
  27. Massimi, P., Pim, D., Bertoli, C., Bouvard, V. & Banks, L. ( 1999; ). Interaction between the HPV-16 E2 transcriptional activator and p53. Oncogene 18, 7748-7754.
    [Google Scholar]
  28. Michelin, D., Gissmann, L., Street, D., Potkul, R. K., Fisher, S., Kaufmann, A. M., Qiao, L. & Schreckenberger, C. ( 1997; ). Regulation of human papillomavirus type 18 in vivo: effects of estrogen and progesterone in transgenic mice. Gynecologic Oncology 66, 202-208.[CrossRef]
    [Google Scholar]
  29. Michnovicz, J. J. & Bradlow, H. L. ( 1990; ). Induction of estradiol metabolism by dietary indole-3-carbinol in humans. Journal of the National Cancer Institute 82, 947-949.[CrossRef]
    [Google Scholar]
  30. Mitrani-Rosenbaum, S., Tsvieli, R. & Tur-Kaspa, R. ( 1989; ). Oestrogen stimulates differential transcription of human papillomavirus type 16 in SiHa cervical carcinoma cells. Journal of General Virology 70, 2227-2232.[CrossRef]
    [Google Scholar]
  31. Mittal, R., Tsutsumi, K., Pater, A. & Pater, M. M. ( 1993; ). Human papillomavirus type 16 expression in cervical keratinocytes: role of progesterone and glucocorticoid hormones. Obstetrics and Gynecology 81, 5-12.
    [Google Scholar]
  32. Mosmann, T. ( 1983; ). Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of Immunological Methods 65, 55-63.[CrossRef]
    [Google Scholar]
  33. Nair, P., Nair, K. M., Jayaprakash, P. G. & Pillai, M. R. ( 1999; ). Decreased programmed cell death in the uterine cervix associated with high risk human papillomavirus infection. Pathology Oncology Research 5, 95-103.[CrossRef]
    [Google Scholar]
  34. Newfield, L., Bradlow, H. L., Sepkovic, D. W. & Auborn, K. ( 1998; ). Estrogen metabolism and the malignant potential of human papillomavirus immortalized keratinocytes. Proceedings of the Society for Experimental Biology and Medicine 217, 322-326.[CrossRef]
    [Google Scholar]
  35. Pater, A., Bayatpour, M. & Pater, M. M. ( 1990; ). Oncogenic transformation by human papillomavirus type 16 deoxyribonucleic acid in the presence of progesterone or progestins from oral contraceptives. American Journal of Obstetrics and Gynecology 162, 1099-1103.[CrossRef]
    [Google Scholar]
  36. Qin, X.-Q., Livingston, D. M., Kaelin, W. G.Jr & Adams, P. D. ( 1994; ). Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis. Proceedings of the National Academy of Sciences, USA 91, 10918-10922.[CrossRef]
    [Google Scholar]
  37. Rando, R. F., Lindheim, S., Hasty, L., Sedlacek, T. V., Woodland, M. & Eder, C. ( 1989; ). Increased frequency of detection of human papillomavirus deoxyribonucleic acid in exfoliated cervical cells during pregnancy. American Journal of Obstetrics and Gynecology 161, 50-55.[CrossRef]
    [Google Scholar]
  38. Sanchez-Perez, A.-M., Soriano, S., Clarke, A. R. & Gaston, K. ( 1997; ). Disruption of the human papillomavirus type 16 E2 gene protects cervical carcinoma cells from E2F-induced apoptosis. Journal of General Virology 78, 3009-3018.
    [Google Scholar]
  39. Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J. & Howley, P. M. ( 1990; ). The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63, 1129-1136.[CrossRef]
    [Google Scholar]
  40. Schneider, A., Hotz, M. & Gissmann, L. ( 1987; ). Increased prevalence of human papillomaviruses in the lower genital tract of pregnant women. International Journal of Cancer 40, 198-201.[CrossRef]
    [Google Scholar]
  41. Schneider-Maunoury, S., Croissant, O. & Orth, G. ( 1987; ). Integration of human papillomavirus type 16 DNA sequences: a possible early event in the progression of genital tumors. Journal of Virology 61, 3295-3298.
    [Google Scholar]
  42. Selvey, L. A., Dunn, L. A., Tindle, R. W., Park, D. S. & Frazer, I. H. ( 1994; ). Human papillomavirus (HPV) type 18 E7 protein is a short-lived steroid-inducible phosphoprotein in HPV-transformed cell lines. Journal of General Virology 75, 1647-1653.[CrossRef]
    [Google Scholar]
  43. Swaneck, G. E. & Fishman, J. ( 1988; ). Covalent binding of the endogenous estrogen 16 alpha-hydroxyestrone to estradiol receptor in human breast cancer cells: characterization and intranuclear localization. Proceedings of the National Academy of Sciences, USA 85, 7831-7835.[CrossRef]
    [Google Scholar]
  44. Telang, N. T., Suto, A., Wong, G. Y., Osborne, M. P. & Bradlow, H. L. ( 1992; ). Induction by estrogen metabolite 16 alpha-hydroxyestrone of genotoxic damage and aberrant proliferation in mouse mammary epithelial cells. Journal of the National Cancer Institute 84, 634-638.[CrossRef]
    [Google Scholar]
  45. Thierry, F. (1996). HPV proteins in the control of HPV transcription. In Papillomavirus Reviews: Current Research on Papillomaviruses, pp. 21–29. Edited by C. Lacey. Leeds: Leeds University Press.
  46. van Ranst, M., Tachezy, R. & Burk, R. D. ( 1996; ). Human papillomaviruses: a neverending story? In Papillomavirus Reviews: Current Research on Papillomaviruses , pp. 1-19. Edited by C. Lacey. Leeds:Leeds University Press.
  47. Walboomers, J. M. M., Jacobs, M. V., Manos, M. M., Bosch, F. X., Kummer, J., Shah, K. V., Snijders, P. J. F., Peto, J., Chris, J. L. M., Meijer, C. J. L. M. & Muñoz, N. ( 1999; ). Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. Journal of Pathology 189, 12-19.[CrossRef]
    [Google Scholar]
  48. Webster, K., Parish, J., Pandya, M., Stern, P. L., Clarke, A. R. & Gaston, K. ( 2000; ). The HPV 16 E2 protein induces apoptosis in the absence of other HPV proteins and via a p53-dependent pathway. Journal of Biological Chemistry 275, 87-94.[CrossRef]
    [Google Scholar]
  49. Werness, B. A., Levine, A. J. & Howley, P. M. ( 1990; ). Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248, 76-79.[CrossRef]
    [Google Scholar]
  50. Wu, X. & Levine, A. J. ( 1994; ). p53 and E2F-1 cooperate to mediate apoptosis. Proceedings of the National Academy of Sciences, USA 91, 3602-3606.[CrossRef]
    [Google Scholar]
  51. Yuan, F., Auborn, K. & James, C. ( 1999a; ). Altered growth and viral gene expression in human papillomavirus type 16-containing cancer cell lines treated with progesterone. Cancer Investigation 17, 19-29.[CrossRef]
    [Google Scholar]
  52. Yuan, F., Chen, D., Liu, K., Sepkovic, D. W., Bradlow, H. L. & Auborn, K. ( 1999b; ). Anti-estrogenic activities of indole-3-carbinol in cervical cells: implication for prevention of cervical cancer. Anticancer Research 19, 1-8.
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-82-1-201
Loading
/content/journal/jgv/10.1099/0022-1317-82-1-201
Loading

Data & Media loading...

Most cited articles

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error