International Journal of Radiation Oncology * Biology * Physics
Volume 74, Issue 3 , Pages 928-933 , 1 July 2009

Radiation Response in Two HPV-Infected Head-and-Neck Cancer Cell Lines in Comparison to a Non–HPV-Infected Cell Line and Relationship to Signaling Through AKT

  • Anjali K. Gupta, M.D.

      Affiliations

    • Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA
    • Corresponding Author InformationReprint requests to: Anjali K. Gupta, M.D., Department of Radiation Oncology, University of Iowa, Hospitals and Clinics, 200 Hawkins Drive, 1625 PFP LLWA, Iowa City, IA 52242. Tel: (319) 384-6135; Fax: (319) 356-1530
  • ,
  • John H. Lee, M.D.

      Affiliations

    • Sanford ENT-H&N Surgery, Sanford Cancer Research, Sioux Falls, SD
  • ,
  • Werner W. Wilke, M.D., Ph.D.

      Affiliations

    • Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA
  • ,
  • Harry Quon, M.D.

      Affiliations

    • Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA
  • ,
  • Gareth Smith, B.A.

      Affiliations

    • Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA
  • ,
  • Amit Maity, M.D., Ph.D.

      Affiliations

    • Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA
  • ,
  • John M. Buatti, M.D.

      Affiliations

    • Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA
  • ,
  • Douglas R. Spitz, Ph.D.

      Affiliations

    • Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA

Received 18 November 2008 ,Revised 10 February 2009 ,Accepted 2 March 2009.

References 

  1. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12–19
  2. Dahlstrom KR, Adler-Storthz K, Etzel CJ, et al. Human papillomavirus type 16 infection and squamous cell carcinoma of the head and neck in never-smokers: A matched pair analysis. Clin Cancer Res. 2003;9:2620–2626
  3. D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356:1944–1956
  4. Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100:261–269
  5. Williams AT, Sexton CJ, Sinclair AL, et al. Retention of low copy number human papillomavirus DNA in cultured cutaneous and mucosal wart keratinocytes. J Gen Virol. 1994;75(Pt 3):505–511
  6. Atula S, Grenman R, Kujari H, et al. Detection of human papillomavirus (HPV) in laryngeal carcinoma cell lines provides evidence for a heterogeneic cell population. Eur J Cancer. 1999;35:825–832
  7. Incassati A, Patel D, McCance DJ. Induction of tetraploidy through loss of p53 and upregulation of Plk1 by human papillomavirus type-16 E6. Oncogene. 2006;25:2444–2451
  8. Padilla LA, Leung BS, Carson LF. Evidence of an association between human papillomavirus and impaired chemotherapy-induced apoptosis in cervical cancer cells. Gynecol Oncol. 2002;85:59–66
  9. Hoffmann TK, Sonkoly E, Hauser U, et al. Alterations in the p53 pathway and their association with radio- and chemosensitivity in head and neck squamous cell carcinoma. Oral Oncol. 2008;44:1100–1109
  10. Saxena A, Yashar C, Taylor DD, et al. Cellular response to chemotherapy and radiation in cervical cancer. Am J Obstet Gynecol. 2005;192:1399–1403
  11. Li W, Thompson CH, Cossart YE, et al. The expression of key cell cycle markers and presence of human papillomavirus in squamous cell carcinoma of the tonsil. Head Neck. 2004;26:1–9
  12. Licitra L, Perrone F, Bossi P, et al. High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol. 2006;24:5630–5636
  13. Reimers N, Kasper HU, Weissenborn SJ, et al. Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer. Int J Cancer. 2007;120:1731–1738
  14. Sisk EA, Soltys SG, Zhu S, et al. Human papillomavirus and p53 mutational status as prognostic factors in head and neck carcinoma. Head Neck. 2002;24:841–849
  15. Gupta AK, Bakanauskas VJ, Cerniglia GJ, et al. The Ras radiation resistance pathway. Cancer Res. 2001;61:4278–4282
  16. Grana TM, Rusyn EV, Zhou H, et al. Ras mediates radioresistance through both phosphatidylinositol 3-kinase-dependent and Raf-dependent but mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-independent signaling pathways. Cancer Res. 2002;62:4142–4150
  17. Gupta AK, Cerniglia GJ, Mick R, et al. HIV protease inhibitors block Akt signaling and radiosensitize tumor cells both in vitro and in vivo. Cancer Res. 2005;65:8256–8265
  18. Cuneo KC, Tu T, Geng L, et al. HIV protease inhibitors enhance the efficacy of irradiation. Cancer Res. 2007;67:4886–4893
  19. Weichselbaum RR, Dahlberg W, Beckett M, et al. Radiation-resistant and repair-proficient human tumor cells may be associated with radiotherapy failure in head- and neck-cancer patients. Proc Natl Acad Sci U S A. 1986;83:2684–2688
  20. Spanos WC, Hoover A, Harris GF, et al. The PDZ binding motif of human papillomavirus type 16 E6 induces PTPN13 loss, which allows anchorage-independent growth and synergizes with ras for invasive growth. J Virol. 2008;82:2493–2500
  21. Ferris RL, Martinez I, Sirianni N, et al. Human papillomavirus-16 associated squamous cell carcinoma of the head and neck (SCCHN): A natural disease model provides insights into viral carcinogenesis. Eur J Cancer. 2005;41:807–815
  22. Hanada M, Feng J, Hemmings BA. Structure, regulation and function of PKB/AKT—a major therapeutic target. Biochim Biophys Acta. 2004;1697:3–16
  23. Scheid MP, Woodgett JR. Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett. 2003;546:108–112
  24. Jacinto E, Facchinetti V, Liu D, et al. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006;127:125–137
  25. Odriozola L, Singh G, Hoang T, et al. Regulation of PTEN activity by its carboxyl-terminal autoinhibitory domain. J Biol Chem. 2007;282:23306–23315
  26. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567–578
  27. Shillitoe EJ, Noonan S. Strength and specificity of different gene promoters in oral cancer cells. Oral Oncol. 2000;36:214–220
  28. Scheffner M, Whitaker NJ. Human papillomavirus-induced carcinogenesis and the ubiquitin-proteasome system. Semin Cancer Biol. 2003;13:59–67
  29. Sionov RV, Haupt Y. The cellular response to p53: the decision between life and death. Oncogene. 1999;18:6145–6157
  30. Komarova EA, Kondratov RV, Wang K, et al. Dual effect of p53 on radiation sensitivity in vivo: p53 promotes hematopoietic injury, but protects from gastro-intestinal syndrome in mice. Oncogene. 2004;23:3265–3271
  31. Gupta AK, McKenna WG, Weber CN, et al. Local recurrence in head and neck cancer: Relationship to radiation resistance and signal transduction. Clin Cancer Res. 2002;8:885–892
  32. Gupta AK, Soto DE, Feldman MD, et al. Signaling pathways in NSCLC as a predictor of outcome and response to therapy. Lung. 2004;182:151–162
  33. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501
  34. Leslie NR, Batty IH, Maccario H, et al. Understanding PTEN regulation: PIP2, polarity and protein stability. Oncogene. 2008;27:5464–5476
  35. Gupta AK, Li B, Cerniglia GJ, et al. The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response. Neoplasia. 2007;9:271–278
  36. Hubbert NL, Sedman SA, Schiller JT. Human papillomavirus type 16 E6 increases the degradation rate of p53 in human keratinocytes. J Virol. 1992;66:6237–6241
  37. Harris GFt, Anderson ME, Lee JH. The effect of proteasome inhibition on p53 degradation and proliferation in tonsil epithelial cells. Arch Otolaryngol Head Neck Surg. 2008;134:157–163
  38. Brunner TB, Geiger M, Grabenbauer GG, et al. Phase I trial of the human immunodeficiency virus protease inhibitor nelfinavir and chemoradiation for locally advanced pancreatic cancer. J Clin Oncol. 2008;26:2699–2706

 Supported by NIH grant R21 CA121580-01A1 (A.K.G.).

 Presented at 50th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Boston, MA, September 21–25, 2008.

 Anjali K. Gupta has a use patent pending on Nelfinavir as a radiation sensitizer. No other conflicts of interest to report.

PII: S0360-3016(09)00363-0

doi: 10.1016/j.ijrobp.2009.03.004

International Journal of Radiation Oncology * Biology * Physics
Volume 74, Issue 3 , Pages 928-933 , 1 July 2009