Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Apr 27;82(10):1709–1716. doi: 10.1054/bjoc.2000.1114

Inhibition of radiation-induced apoptosis by dexamethasone in cervical carcinoma cell lines depends upon increased HPV E6/E7

M C Kamradt 1,2, N Mohideen 2, E Krueger 2, S Walter 2, A T M Vaughan 2
PMCID: PMC2374500  PMID: 10817508

Abstract

Through a glucocorticoid-responsive promoter, glucocorticoids can regulate the transcription of the human papillomavirus (HPV) E6 and E7 viral genes which target the tumour suppressor proteins p53 and Rb respectively. In C4-1 cells, the glucocorticoid dexamethasone up-regulated HPV E6/E7 mRNA and decreased radiation-induced apoptosis. In contrast, dexamethasone had no effect on apoptosis of cells that either lack the HPV genome (C33-a) or in which HPV E6/E7 transcription is repressed by dexamethasone (SW756). Irradiated C4-1 cells showed increased p53 expression, while dexamethasone treatment prior to irradiation decreased p53 protein expression. In addition, p21 mRNA was regulated by irradiation and dexamethasone in accordance with the observed changes in p53. Overall, glucocorticoids decreased radiation-induced apoptosis in cervical carcinoma cells which exhibit increased HPV E6/E7 transcription and decreased p53 expression. Therefore, in HPV-infected cervical epithelial cells, p53-dependent apoptosis appears to depend upon the levels of HPV E6/E7 mRNA. © 2000 Cancer Research Campaign

Keywords: HPV, dexamethasone, apoptosis, cervical carcinoma, p53

Full Text

The Full Text of this article is available as a PDF (154.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Almasan A., Linke S. P., Paulson T. G., Huang L. C., Wahl G. M. Genetic instability as a consequence of inappropriate entry into and progression through S-phase. Cancer Metastasis Rev. 1995 Mar;14(1):59–73. doi: 10.1007/BF00690212. [DOI] [PubMed] [Google Scholar]
  2. Band V., De Caprio J. A., Delmolino L., Kulesa V., Sager R. Loss of p53 protein in human papillomavirus type 16 E6-immortalized human mammary epithelial cells. J Virol. 1991 Dec;65(12):6671–6676. doi: 10.1128/jvi.65.12.6671-6676.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bracey T. S., Miller J. C., Preece A., Paraskeva C. Gamma-radiation-induced apoptosis in human colorectal adenoma and carcinoma cell lines can occur in the absence of wild type p53. Oncogene. 1995 Jun 15;10(12):2391–2396. [PubMed] [Google Scholar]
  4. Butz K., Geisen C., Ullmann A., Spitkovsky D., Hoppe-Seyler F. Cellular responses of HPV-positive cancer cells to genotoxic anti-cancer agents: repression of E6/E7-oncogene expression and induction of apoptosis. Int J Cancer. 1996 Nov 15;68(4):506–513. doi: 10.1002/(SICI)1097-0215(19961115)68:4<506::AID-IJC17>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  5. Butz K., Shahabeddin L., Geisen C., Spitkovsky D., Ullmann A., Hoppe-Seyler F. Functional p53 protein in human papillomavirus-positive cancer cells. Oncogene. 1995 Mar 2;10(5):927–936. [PubMed] [Google Scholar]
  6. Butz K., Whitaker N., Denk C., Ullmann A., Geisen C., Hoppe-Seyler F. Induction of the p53-target gene GADD45 in HPV-positive cancer cells. Oncogene. 1999 Apr 8;18(14):2381–2386. doi: 10.1038/sj.onc.1202557. [DOI] [PubMed] [Google Scholar]
  7. Clarke A. R., Purdie C. A., Harrison D. J., Morris R. G., Bird C. C., Hooper M. L., Wyllie A. H. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 1993 Apr 29;362(6423):849–852. doi: 10.1038/362849a0. [DOI] [PubMed] [Google Scholar]
  8. Crook T., Tidy J. A., Vousden K. H. Degradation of p53 can be targeted by HPV E6 sequences distinct from those required for p53 binding and trans-activation. Cell. 1991 Nov 1;67(3):547–556. doi: 10.1016/0092-8674(91)90529-8. [DOI] [PubMed] [Google Scholar]
  9. Demers G. W., Foster S. A., Halbert C. L., Galloway D. A. Growth arrest by induction of p53 in DNA damaged keratinocytes is bypassed by human papillomavirus 16 E7. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4382–4386. doi: 10.1073/pnas.91.10.4382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dyson N., Howley P. M., Münger K., Harlow E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science. 1989 Feb 17;243(4893):934–937. doi: 10.1126/science.2537532. [DOI] [PubMed] [Google Scholar]
  11. Gloss B., Bernard H. U., Seedorf K., Klock G. The upstream regulatory region of the human papilloma virus-16 contains an E2 protein-independent enhancer which is specific for cervical carcinoma cells and regulated by glucocorticoid hormones. EMBO J. 1987 Dec 1;6(12):3735–3743. doi: 10.1002/j.1460-2075.1987.tb02708.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Harper J. W., Adami G. R., Wei N., Keyomarsi K., Elledge S. J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805–816. doi: 10.1016/0092-8674(93)90499-g. [DOI] [PubMed] [Google Scholar]
  13. Hickman E. S., Bates S., Vousden K. H. Perturbation of the p53 response by human papillomavirus type 16 E7. J Virol. 1997 May;71(5):3710–3718. doi: 10.1128/jvi.71.5.3710-3718.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hoppe-Seyler F., Butz K. Cellular control of human papillomavirus oncogene transcription. Mol Carcinog. 1994 Jul;10(3):134–141. doi: 10.1002/mc.2940100304. [DOI] [PubMed] [Google Scholar]
  15. Iglesias M., Yen K., Gaiotti D., Hildesheim A., Stoler M. H., Woodworth C. D. Human papillomavirus type 16 E7 protein sensitizes cervical keratinocytes to apoptosis and release of interleukin-1alpha. Oncogene. 1998 Sep 10;17(10):1195–1205. doi: 10.1038/sj.onc.1202054. [DOI] [PubMed] [Google Scholar]
  16. Kangas A., Nicholson D. W., Hölttä E. Involvement of CPP32/Caspase-3 in c-Myc-induced apoptosis. Oncogene. 1998 Jan 22;16(3):387–398. doi: 10.1038/sj.onc.1201779. [DOI] [PubMed] [Google Scholar]
  17. Kessis T. D., Slebos R. J., Nelson W. G., Kastan M. B., Plunkett B. S., Han S. M., Lorincz A. T., Hedrick L., Cho K. R. Human papillomavirus 16 E6 expression disrupts the p53-mediated cellular response to DNA damage. Proc Natl Acad Sci U S A. 1993 May 1;90(9):3988–3992. doi: 10.1073/pnas.90.9.3988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lazo P. A. The molecular genetics of cervical carcinoma. Br J Cancer. 1999 Aug;80(12):2008–2018. doi: 10.1038/sj.bjc.6690635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lechner M. S., Laimins L. A. Inhibition of p53 DNA binding by human papillomavirus E6 proteins. J Virol. 1994 Jul;68(7):4262–4273. doi: 10.1128/jvi.68.7.4262-4273.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lowe S. W., Ruley H. E. Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis. Genes Dev. 1993 Apr;7(4):535–545. doi: 10.1101/gad.7.4.535. [DOI] [PubMed] [Google Scholar]
  21. Lowe S. W., Schmitt E. M., Smith S. W., Osborne B. A., Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature. 1993 Apr 29;362(6423):847–849. doi: 10.1038/362847a0. [DOI] [PubMed] [Google Scholar]
  22. Mittal R., Tsutsumi K., Pater A., Pater M. M. Human papillomavirus type 16 expression in cervical keratinocytes: role of progesterone and glucocorticoid hormones. Obstet Gynecol. 1993 Jan;81(1):5–12. [PubMed] [Google Scholar]
  23. Morgenbesser S. D., Williams B. O., Jacks T., DePinho R. A. p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens. Nature. 1994 Sep 1;371(6492):72–74. doi: 10.1038/371072a0. [DOI] [PubMed] [Google Scholar]
  24. Naumann U., Durka S., Weller M. Dexamethasone-mediated protection from drug cytotoxicity: association with p21WAF1/CIP1 protein accumulation? Oncogene. 1998 Sep 24;17(12):1567–1575. doi: 10.1038/sj.onc.1202071. [DOI] [PubMed] [Google Scholar]
  25. Pan H., Griep A. E. Altered cell cycle regulation in the lens of HPV-16 E6 or E7 transgenic mice: implications for tumor suppressor gene function in development. Genes Dev. 1994 Jun 1;8(11):1285–1299. doi: 10.1101/gad.8.11.1285. [DOI] [PubMed] [Google Scholar]
  26. Pan H., Griep A. E. Temporally distinct patterns of p53-dependent and p53-independent apoptosis during mouse lens development. Genes Dev. 1995 Sep 1;9(17):2157–2169. doi: 10.1101/gad.9.17.2157. [DOI] [PubMed] [Google Scholar]
  27. Puthenveettil J. A., Frederickson S. M., Reznikoff C. A. Apoptosis in human papillomavirus16 E7-, but not E6-immortalized human uroepithelial cells. Oncogene. 1996 Sep 19;13(6):1123–1131. [PubMed] [Google Scholar]
  28. Radford I. R. p53 status, DNA double-strand break repair proficiency, and radiation response of mouse lymphoid and myeloid cell lines. Int J Radiat Biol. 1994 Nov;66(5):557–560. doi: 10.1080/09553009414551621. [DOI] [PubMed] [Google Scholar]
  29. Scheffner M., Münger K., Byrne J. C., Howley P. M. The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5523–5527. doi: 10.1073/pnas.88.13.5523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Scheffner M., Werness B. A., Huibregtse J. M., Levine A. J., Howley P. M. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell. 1990 Dec 21;63(6):1129–1136. doi: 10.1016/0092-8674(90)90409-8. [DOI] [PubMed] [Google Scholar]
  31. Shaw P., Bovey R., Tardy S., Sahli R., Sordat B., Costa J. Induction of apoptosis by wild-type p53 in a human colon tumor-derived cell line. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4495–4499. doi: 10.1073/pnas.89.10.4495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Stern E., Forsythe A. B., Youkeles L., Coffelt C. F. Steroid contraceptive use and cervical dysplasia: increased risk of progression. Science. 1977 Jun 24;196(4297):1460–1462. doi: 10.1126/science.867043. [DOI] [PubMed] [Google Scholar]
  33. Strasser A., Harris A. W., Jacks T., Cory S. DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2. Cell. 1994 Oct 21;79(2):329–339. doi: 10.1016/0092-8674(94)90201-1. [DOI] [PubMed] [Google Scholar]
  34. Stöppler H., Stöppler M. C., Johnson E., Simbulan-Rosenthal C. M., Smulson M. E., Iyer S., Rosenthal D. S., Schlegel R. The E7 protein of human papillomavirus type 16 sensitizes primary human keratinocytes to apoptosis. Oncogene. 1998 Sep 10;17(10):1207–1214. doi: 10.1038/sj.onc.1202053. [DOI] [PubMed] [Google Scholar]
  35. Thomas M., Massimi P., Jenkins J., Banks L. HPV-18 E6 mediated inhibition of p53 DNA binding activity is independent of E6 induced degradation. Oncogene. 1995 Jan 19;10(2):261–268. [PubMed] [Google Scholar]
  36. Von Knebel Doeberitz M., Koch S., Drzonek H., Zur Hausen H. Glucocorticoid hormones reduce the expression of major histocompatibility class I antigens on human epithelial cells. Eur J Immunol. 1990 Jan;20(1):35–40. doi: 10.1002/eji.1830200106. [DOI] [PubMed] [Google Scholar]
  37. Walboomers J. M., Jacobs M. V., Manos M. M., Bosch F. X., Kummer J. A., Shah K. V., Snijders P. J., Peto J., Meijer C. J., Muñoz N. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999 Sep;189(1):12–19. doi: 10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F. [DOI] [PubMed] [Google Scholar]
  38. Wang Y., Okan I., Pokrovskaja K., Wiman K. G. Abrogation of p53-induced G1 arrest by the HPV 16 E7 protein does not inhibit p53-induced apoptosis. Oncogene. 1996 Jun 20;12(12):2731–2735. [PubMed] [Google Scholar]
  39. Werness B. A., Levine A. J., Howley P. M. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science. 1990 Apr 6;248(4951):76–79. doi: 10.1126/science.2157286. [DOI] [PubMed] [Google Scholar]
  40. White E. Life, death, and the pursuit of apoptosis. Genes Dev. 1996 Jan 1;10(1):1–15. doi: 10.1101/gad.10.1.1. [DOI] [PubMed] [Google Scholar]
  41. Yonish-Rouach E., Resnitzky D., Lotem J., Sachs L., Kimchi A., Oren M. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature. 1991 Jul 25;352(6333):345–347. doi: 10.1038/352345a0. [DOI] [PubMed] [Google Scholar]
  42. Yu Y., Little J. B. p53 is involved in but not required for ionizing radiation-induced caspase-3 activation and apoptosis in human lymphoblast cell lines. Cancer Res. 1998 Oct 1;58(19):4277–4281. [PubMed] [Google Scholar]
  43. el-Deiry W. S., Tokino T., Velculescu V. E., Levy D. B., Parsons R., Trent J. M., Lin D., Mercer W. E., Kinzler K. W., Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817–825. doi: 10.1016/0092-8674(93)90500-p. [DOI] [PubMed] [Google Scholar]
  44. von Knebel Doeberitz M., Bauknecht T., Bartsch D., zur Hausen H. Influence of chromosomal integration on glucocorticoid-regulated transcription of growth-stimulating papillomavirus genes E6 and E7 in cervical carcinoma cells. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1411–1415. doi: 10.1073/pnas.88.4.1411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. von Knebel Doeberitz M., Oltersdorf T., Schwarz E., Gissmann L. Correlation of modified human papilloma virus early gene expression with altered growth properties in C4-1 cervical carcinoma cells. Cancer Res. 1988 Jul 1;48(13):3780–3786. [PubMed] [Google Scholar]
  46. von Knebel Doeberitz M., Rittmüller C., Aengeneyndt F., Jansen-Dürr P., Spitkovsky D. Reversible repression of papillomavirus oncogene expression in cervical carcinoma cells: consequences for the phenotype and E6-p53 and E7-pRB interactions. J Virol. 1994 May;68(5):2811–2821. doi: 10.1128/jvi.68.5.2811-2821.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. von Knebel Doeberitz M., Rittmüller C., zur Hausen H., Dürst M. Inhibition of tumorigenicity of cervical cancer cells in nude mice by HPV E6-E7 anti-sense RNA. Int J Cancer. 1992 Jul 9;51(5):831–834. doi: 10.1002/ijc.2910510527. [DOI] [PubMed] [Google Scholar]
  48. zur Hausen H. Human papillomaviruses in the pathogenesis of anogenital cancer. Virology. 1991 Sep;184(1):9–13. doi: 10.1016/0042-6822(91)90816-t. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES