Molecular Medicine

, Volume 18, Issue 2, pp 244–249 | Cite as

Constitutive Overexpression of the Oncogene Racl in the Airway of Recurrent Respiratory Papillomatosis Patients Is a Targetable Host-Susceptibility Factor

  • Alexandra V. Lucs
  • Rong Wu
  • Virginia Mullooly
  • Allan L. Abramson
  • Bettie M. Steinberg
Research Article


Recurrent respiratory papillomatosis (RRP) is caused by human papillomaviruses (HPVs), primarily types 6 and 11. The disease is characterized by multiple recurrences of airway papillomas, resulting in high levels of morbidity and significant mortality. The prevalence of latent HPV in the larynx of the general population is much greater than the prevalence of RRP, suggesting a host-susceptibility factor for disease. We report that the oncogene Rac1 and its downstream product cyclooxygenase-2 (COX-2) are both constitutively expressed at high levels throughout the airway of these patients, independent of active HPV infection. Use of the COX-2 inhibitor celecoxib in primary papilloma cell culture resulted in the downregulation of HPV transcription. Furthermore, a proof-of-principle study treating three patients with severe RRP with celecoxib resulted in remission of disease in all cases. Therefore, we have identified the first pharmacologically targetable host-susceptibility pathway that contributes to RRP recurrence.



We gratefully acknowledge Marc Symons for helpful suggestions and critical reading of the manuscript. This work was supported by grants 5R01DC00203, 5R01DC008579, 1R01DC008579-S1 and 1F32DC011446 from the National Institute on Deafness and Other Communication Disorders.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Deafness and Other Communication Disorders or the National Institutes of Health. Celecoxib and matching placebo were provided by grant 2004-0029 (WS287683) from Pfizer Global Pharmaceuticals, New York, New York, USA.

Celecoxib was used for the clinical study and was obtained through a grant from Pfizer.


  1. 1.
    Derkay CS, Wiatrak B. (2008) Recurrent respiratory papillomatosis: a review. Laryngoscope. 118:1236–47.CrossRefGoogle Scholar
  2. 2.
    Johnston D, Hall H, DiLorenzo TP, Steinberg BM. (1999) Elevation of the epidermal growth factor receptor and dependent signaling in human papillomavirus-infected laryngeal papillomas. Cancer Res. 59:968–74.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Wu R, Abramson AL, Shikowitz MJ, Dannenberg AJ, Steinberg BM. (2005) Epidermal growth factor-induced cyclooxygenase-2 expression is mediated through phosphatidylinositol-3 kinase, not mitogen-activated protein/extracellular signal-regulated kinase kinase, in recurrent respiratory papillomas. Clin. Cancer Res. 11:6155–61.CrossRefGoogle Scholar
  4. 4.
    Wu R, Coniglio SJ, Chan A, Symons MH, Steinberg BM. (2007) Up-regulation of Racl by epidermal growth factor mediates COX-2 expression in recurrent respiratory papillomas. Mol. Med. 13:143–50.CrossRefGoogle Scholar
  5. 5.
    Wheeler DL, Dunn EF, Harari PM. Understanding resistance to EGFR inhibitors: impact on future treatment strategies. Nat. Rev. Clin. Oncol. 7:493–507.Google Scholar
  6. 6.
    Bosco EE, Mulloy JC, Zheng Y. (2009) Racl GT-Pase: a “Rac” of all trades. Cell. Mol. Life Sci. 66:370–4.CrossRefGoogle Scholar
  7. 7.
    Vega FM, Ridley AJ. (2008) Rho GTPases in cancer cell biology. FEBS Lett. 582:2093–101.CrossRefGoogle Scholar
  8. 8.
    Greenhough A, et al. (2009) The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis. 30:377–86.CrossRefGoogle Scholar
  9. 9.
    Mammas IN, Sourvinos G, Michael C, Spandidos DA. (2006) Human papilloma virus in hyperplastic tonsillar and adenoid tissues in children. Pediatr. Infect. Dis. J. 25:1158–62.CrossRefGoogle Scholar
  10. 10.
    Smith EM, et al. (2007) Prevalence of human papillomavirus in the oral cavity/oropharynx in a large population of children and adolescents. Pediatr. Infect. Dis. J. 26:836–40.CrossRefGoogle Scholar
  11. 11.
    Steinberg BM, Abramson AL, Meade RP. (1982) Culture of human laryngeal papilloma cells in vitro. Otolaryngol. Head Neck Surg. 90:728–35.CrossRefGoogle Scholar
  12. 12.
    Laborda J. (1991) 36B4 cDNA used as an estradiol-independent mRNA control is the cDNA for human acidic ribosomal phosphoprotein PO. Nucleic Acids Res. 19:3998.CrossRefGoogle Scholar
  13. 13.
    Shikowitz MJ, Abramson AL, Freeman K, Steinberg BM, Nouri M. (1998) Efficacy of DHE photodynamic therapy for respiratory papillomatosis: immediate and long-term results. Laryngoscope. 108:962–7.CrossRefGoogle Scholar
  14. 14.
    Shikowitz MJ, et al. (2005) Clinical trial of photodynamic therapy with meso-tetra (hydroxyphenyl) chlorin for respiratory papillomatosis. Arch. Otolaryngol. Head Neck Surg. 131:99–105.CrossRefGoogle Scholar
  15. 15.
    Abramson AL, Nouri M, Mullooly V, Fisch G, Steinberg BM. (2004) Latent human papillomavirus infection is comparable in the larynx and trachea. J. Med. Virol. 72:473–7.CrossRefGoogle Scholar
  16. 16.
    Westwick JK, et al. (1997) Rac regulation of transformation, gene expression, and actin organization by multiple, PAK-independent pathways. Mol. Cell. Biol. 17:1324–35.CrossRefGoogle Scholar
  17. 17.
    Cohen EG, et al. (2003) Microsomal prostaglandin E synthase-l is overexpressed in head and neck squamous cell carcinoma. Clin. Cancer Res. 9:3425–30.PubMedGoogle Scholar
  18. 18.
    Yoshimatsu K, et al. (2001) Inducible prostaglandin E synthase is overexpressed in non-small cell lung cancer. Clin. Cancer Res. 7:2669–74.PubMedGoogle Scholar
  19. 19.
    Xiao H, Yang CS. (2008) Combination regimen with statins and NSAIDs: a promising strategy for cancer chemoprevention. Int. J. Cancer. 123:983–90.CrossRefGoogle Scholar
  20. 20.
    Hawley-Nelson P, Vousden KH, Hubbert NL, Lowy DR, Schiller JT. (1989) HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. EMBO J. 8:3905–10.CrossRefGoogle Scholar
  21. 21.
    Munger K, Phelps WC, Bubb V, Howley PM, Schlegel R. (1989) The E6 and E7 genes of the human papillomavirus type l6 together are necessary and sufficient for transformation of primary human keratinocytes. J. Virol. 63:4417–21.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Gomez del Pulgar T, Benitah SA, Valeron PF, Espina C, Lacal JC. (2005) Rho GTPase expression in tumourigenesis: evidence for a significant link. Bioessays. 27:602–13.CrossRefGoogle Scholar
  23. 23.
    Banerjee AG, Gopalakrishnan VK, Bhattacharya I, Vishwanatha JK. (2002) Deregulated cyclooxygenase-2 expression in oral premalignant tissues. Mol. Cancer Ther. 1:1265–71.PubMedGoogle Scholar
  24. 24.
    Kulkarni S, et al. (2001) Cyclooxygenase-2 is overexpressed in human cervical cancer. Clin. Cancer Res. 7:429–34.PubMedGoogle Scholar
  25. 25.
    Ferrandina G, et al. (2003) Celecoxib modulates the expression of cyclooxygenase-2, ki67, apoptosis-related marker, and microvessel density in human cervical cancer: a pilot study. Clin. Cancer Res. 9:4324–31.PubMedGoogle Scholar
  26. 26.
    Chan G, et al. (1999) Cyclooxygenase-2 expression is up-regulated in squamous cell carcinoma of the head and neck. Cancer Res. 59:991–4.PubMedGoogle Scholar
  27. 27.
    Renkonen J, Wolff H, Paavonen T. (2002) Expression of cyclo-oxygenase-2 in human tongue carcinoma and its precursor lesions. Virchows Arch. 440:594–7.CrossRefGoogle Scholar
  28. 28.
    Ranelletti FO, et al. (2001) Prognostic significance of cyclooxygenase-2 in laryngeal squamous cell carcinoma. Int. J. Cancer. 95:343–9.CrossRefGoogle Scholar
  29. 29.
    Subbaramaiah K, Dannenberg AJ. (2003) Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol. Sci. 24:96–102.CrossRefGoogle Scholar
  30. 30.
    Limsukon A, Susanto I, Hoo GW, Dubinett SM, Batra RK. (2009) Regression of recurrent respiratory papillomatosis with celecoxib and erlotinib combination therapy. Chest. 136:924–6.CrossRefGoogle Scholar
  31. 31.
    Farley JH, et al. (2006) A randomized doubleblind placebo-controlled phase II trial of the cyclooxygenase-2 inhibitor celecoxib in the treatment of cervical dysplasia. Gynecol. Oncol. 103:425–30.CrossRefGoogle Scholar
  32. 32.
    DeVoti JA, Rosenthal DW, Wu R, Abramson AL, Steinberg BM, Bonagura VR. (2008) Immune dysregulation and tumor-associated gene changes in recurrent respiratory papillomatosis: a paired microarray analysis. Mol. Med. 14:608–17.CrossRefGoogle Scholar
  33. 33.
    Gallagher TQ, Derkay CS. (2009) Pharmacotherapy of recurrent respiratory papillomatosis: an expert opinion. Expert Opin. Pharmacother. 10:645–55.CrossRefGoogle Scholar
  34. 34.
    Solomon SD, et al. (2006) Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation. 114:1028–35.CrossRefGoogle Scholar

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Authors and Affiliations

  • Alexandra V. Lucs
    • 1
  • Rong Wu
    • 1
    • 2
  • Virginia Mullooly
    • 2
  • Allan L. Abramson
    • 1
    • 2
    • 3
  • Bettie M. Steinberg
    • 1
    • 2
    • 3
  1. 1.Feinstein Institute for Medical ResearchNorth Shore-Long Island Jewish (LIJ) Health SystemManhassetUSA
  2. 2.Department of Otolaryngology and Communicative DisordersLong Island Jewish Medical CenterNew Hyde ParkUSA
  3. 3.Hofstra North Shore-LIJ School of MedicineManhassetUSA

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