Abstract
High-risk human papillomaviruses (HPVs) have been associated to the development of cervical and some other human cancers. Most of them express E6 and E7 oncoproteins, able to bind to p53 and retinoblastoma (pRb) tumor suppressor proteins respectively and neutralize their function. Restoration of these pathways by blocking E6 and E7 expression would provide a selective therapeutic effect. Here, we show that a clinically approved antiviral agent Cidofovir reduced E6 and E7 expression in cervical carcinoma Me180 and head and neck squamous cell carcinoma HEP2 cells at the transcriptional level. Cidofovir induced the accumulation of active p53 and pRb associated to induction of cyclin dependent kinase inhibitor p21WAF1/CIP1 in Me180 and HEP2 cells. p53 induction was also shown in Hela HPV-positive cervical carcinoma cell line. In addition, S phase cell cycle accumulation with concomitant decrease of cyclin A expression were associated to the antiproliferative activity of Cidofovir in HPV-treated cells. Combining Cidofovir to irradiation both in vivo and in nude mice xenografts resulted in a marked radiosensitization in HPV-positive cells, which was not observed in virus negative cells. This study provides the basis for a new anticancer strategy to enhance the antitumor effect of ionizing radiation in HPV-related cancers, without increase deleterious effects.
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References
Abdulkarim B, Bourhis J . 2001 Lancet Oncology 2: 622–630
Andrei G, Snoeck R, Piette J, Delvenne P, De Clercq E . 1998 Oncol. Res. 10: 523–531
Alvaraz-Salas LM, Cullinan AE, Siwkowski A, Hampel A, DiaPaolo A . 1998 Proc. Natl. Acad. Sci. USA 95: 1189–1194
Asada M, Yamada T, Ichijo H, Delia D, Miyazono K, Fukumuro K, Mizutani S . 1999 EMBO. J. 18: 1223–1234
Bartek J, Bartkova J, Lukas J . 1997 Exp. Cell. Res. 237: 1–6
Berezutskaya E, Yu B, Morozov A, Raychaudhuri P, Bagchi S . 1997 Cell Growth Differ. 8: 1277–1286
Boyer SN, Wazer DE, Band V . 1996 Cancer Res. 56: 4620–4624
Butz K, Denk C, Ullmann A, Scheffner M, Hoppe-Seyler F . 2000 Proc. Natl. Acad. Sci. USA 6: 6693–6697
Butz K, Shahabeddin L, Geisen C, Spitkovsky D, Ullmann A, Hoppe-Seyler F . 1995 Oncogene 10: 927–936
Cai Z, Capoulade C, Moyret-Lalle C, Amor-Gueret M, Feunteun J, Larsen AK, Paillerets BB, Chouaib S . 1997 Oncogene 15: 2817–2826
Chew YP, Ellis M, Wilkie S, Mittnacht S . 1998 Oncogene 29: 2177–2186
Chiba I, Shindoh M, Yasuda M, Yamazaki Y, Amemiya A, Sato Y, Fujinaga K, Notani K, Fukuda H . 1996 Oncogene 12: 1663–1668
Crook T, Parker GA, Rozycka M, Crossland S, Allday MJ . 1998 Oncogene 16: 1429–1441
Demers GW, Espling E, Harry JB, Etscheid BG, Galloway A . 1996 J. Virol. 70: 6862–6869
DiPaolo JA, Popescu NC, Alvarez L, Woodworth CD . 1993 Crit. Rev. Oncog. 4: 337–3360
El-Deiry WS, Tokino T, Valculescu VE, Levy DB, Parsons R, Trent JM, Lind D, Mercer WE, Kinzler KW, Vogelstein B . 1993 Cell 75: 817–825
Flaman JM, Frebourg T, Moreau V, Charbonnier F, Martin C, Chappuis P, Sappino AP, Limacher IM, Bron L, Benhattar J . 1995 Proc. Natl. Acad. Sci. USA 92: 3963–3967
Francis DA, Schmid SI, Howley PM . 2000 J. Virol. 74: 2679–2686
Freedman DA, Levine AJ . 1998 Mol. Cell. Biol. 18: 7288–7293
Funk JO, Waga S, Harry JB, Espling E, Stillman B, Galloway DA . 1997 Genes Dev. 11: 2090–2100
Gallardo D, Drazan K, McBride W . 1996 Cancer Res. 56: 4891–4903
Gillison ML, Koch WM, Shah KV . 1999 Curr. Opin. Oncol. 11: 1–9
Goodwin EC, DiMaio D . 2000 Proc. Natl. Acad. Sci. USA 97: 12513–12518
Goodwin EC, Yang E, Lee CJ, Lee HW, DiMaio D, Hwang ES . 2000 Proc. Natl. Acad. Sci. USA 97: 10978–10983
Goubin F, Ducommun B . 1995 Oncogene 10: 2281–2287
He Y, Huang L . 1997 Cancer Res. 57: 3993–3993
Hengstermann A, Linares LK, Ciechanover A, Whitaker NJ, Scheffner M . 2001 Proc. Natl. Acad. Sci. USA 98: 1218–1223
Hickman ES, Picksley SM, Vousden KH . 1994 Oncogene 9: 2177–2181
Hietanen S, Lain S, Krausz E, Blattner C, Lane DP . 2000 Proc. Natl. Acad. Sci. USA 97: 8501–8506
Hu G, Liu W, Hanania EG, Fu S, Wang T, Deisseroth AB . 1995 Cancer. Gene. Ther. 2: 19–32
Hwang ES, Naeger LK, DiMaio D . 1996 Oncogene 15: 795–803
Jeon S, Allen-Hoffmann BI, Lambert PF . 1995 J. Virol. 69: 2989–2997
Johnson JA, Gangemi JD . 2000 Antimicrob. Agents. Chemother. 43: 198–205
Jones DL, Alani RM, Munger K . 1997a Genes Dev. 11: 2101–2111
Jones DL, Thompson DA, Munger K . 1997b Virology 239: 97–107
Kaelin Jr WG . 1999 Bioessays 21: 950–958
Kamradt MC, Mohideen N, Krueger E, Walter S, Vaughan AT . 2000 Br. J. Cancer 82: 1709–1716
Knudsen ES, Buckmaster C, Chen TT, Feramisco JR, Wang JY . 1998 Genes Dev. 12: 2278–2292
Knudsen KE, Fribourg AF, Strobeck MW, Blanchard JM, Knudsen ES . 1999 J. Biol. Chem. 274: 27632–27641
Knudsen KE, Booth D, Naderi S, Sever-Chroneos Z, Fribourg AF, Hunton IC, Feramisco JR, Wang JY, Knudsen ES . 2000 Mol. Cell. Biol. 20: 7751–7763
Lazo PA . 1999 Br. J. Cancer 80: 2008–2018
Levine AJ . 1997 Cell 88: 323–331
Liekens S, Verbeken E, De Clercq E, Neyts N . 2001 Int. J. Cancer 92: 161–167
Mantovani F, Banks L . 1999 Oncogene 18: 3309–3315
Moran E . 1993 Curr. Opin. Genet. Dev. 13: 261–291
Neyts J, Sadler R, De Clercq E, Raab-Traub N, Pagano JS . 1998 Cancer Res. 58: 384–388
Pisarev VM, Lee SH, Connelly MC, Fridland A . 1997 Mol. Pharmacol. 52: 63–68
Safrin S, Cherrigton J, Jaffe HS . 1997 Rev. Med. Virol. 7: 145–156
Santin AD, Hermonat PL, Ravaggi A, Chiriva-Internati M, Pecorelli S, Parham GP . 1998 Cancer 83: 2346–2352
Scheffner M, Munger K, Byrne JC, Howley PM . 2000 Proc. Natl. Acad. Sci. USA 88: 5523–5527
Scheffner M, Huibregtse JM, Vierstra RD, Howley PM . 1993 Cell 75: 495–505
Schiffman MH . 1995 J. Nat. Can. Inst. 87: 1345–1347
Slebos RJ, Lee MH, Plunkett BS, Kessis TD, Williams BO, Jacks T, Hedrick L, Kastan MB, Cho KR . 1994 Proc. Natl. Acad. Sci. USA 91: 5320–5324
Smith-McCune K, Kalman D, Robbins C, Shivakumar S, Yuschenkoff L, Bishop JM . 1999 Proc. Natl. Acad. Sci. USA 96: 6999–7004
Spitz FR, Nguyen D, Skibbe JM, Meyn RE, Cristiano RJ, Roth JA . 1996 Clin. Cancer Res. 2: 1665–1671
Steele C, Cowsert LM, Shillitoe EJ . 1993 Cancer Res. 15: 2330–2337
Steele C, Sacks PG, Adler-Storthz K, Shillitoe EJ . 1992 Cancer Res. 52: 4706–4711
Stoppler H, Stoppler MC, Johnson E et al . 1998 Oncogene 17: 1207–1214
Tan TM, Ting RC . 1995 Cancer Res. 55: 4599–4605
Venturini F, Braspenning J, Homann M, Gissmann L, Sczakiel G . 1999 Nucleic Acids Res. 27: 1585–1592
Villa LL . 1997 Adv. Cancer Res. 71: 321–341
von Knebel-Doeberitz M, Oltersdorf T, Schwarz E, Gissmann L . 1988 Cancer Res. 48: 3780–3786
Wu L, Goodwin EC, Naeger LK, Vigo E, Galaktionov K, Helin K, DiMaio D . 2000 Mol. Cell 20: 7059–7067
zur Hausen H . 2000 J. Natl. Cancer Inst. 92: 690–698
Acknowledgements
We are especially grateful to Dr S Chouaïb for his constructive discussion about the experiments and for the critical reading of the manuscript.
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Abdulkarim, B., Sabri, S., Deutsch, E. et al. Antiviral agent Cidofovir restores p53 function and enhances the radiosensitivity in HPV-associated cancers. Oncogene 21, 2334–2346 (2002). https://doi.org/10.1038/sj.onc.1205006
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DOI: https://doi.org/10.1038/sj.onc.1205006
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