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Quercetin elevates p27Kip1 and arrests both primary and HPV16 E6/E7 transformed human keratinocytes in G1

Abstract

Our previous work with primary bovine fibroblasts demonstrated that quercetin, a potent mutagen found in high levels in bracken fern (Pteridium aquilinum), arrested cells in G1 and G2/M, in correlation with p53 activation. The expression of bovine papillomavirus type 4 (BPV-4) E7 overcame this arrest and lead to the development of tumorigenic cells lines (Beniston et al., 2001). Given the possible link between papillomavirus infection, bracken fern in the diet and cancer of the upper gastrointestinal (GI) tract in humans, we investigated whether a similar situation would occur in human cells transformed by human papillomavirus type 16 (HPV-16) oncoproteins. Quercetin arrested primary human foreskin keratinocytes in G1. Arrest was linked to an elevation of the cyclin-dependent kinase inhibitor (cdki) p27Kip1. Expression of the HPV16 E6 and E7 oncoproteins in transformed cells failed to abrogate cell cycle arrest. G1 arrest in the transformed cells was also linked to an increase of p27Kip1 with a concomitant reduction of cyclin E-associated kinase activity. This elevation of p27Kip1 was due not only to increased protein half-life, but also to increased mRNA transcription.

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References

  • Alonso-Amelot ME and Avendano M . (2001). Int. J. Cancer, 91, 252–259.

    Article  Google Scholar 

  • Alonso-Amelot ME, Castillo U, Smith BL and Lauren DR . (1996). Nature, 382, 587.

    Article  CAS  Google Scholar 

  • Arber N, Shapira I, Ratan J, Stern B, Hibshoosh H, Moshkowitz M, Gammon M, Fabian I and Halpern Z . (2000). Gastroenterology, 118, 1045–1050.

    Article  CAS  Google Scholar 

  • Ashby ADM, Meagher L, Campo MS and Finbow ME . (2001). J. Gen. Virol., 82, 2353–2362.

  • Beniston RG, Morgan IM, O'Brien V and Campo MS . (2001). Carcinogenesis, 22, 1069–1076.

    Article  CAS  Google Scholar 

  • Bjieldanes LF and Chang GW . (1977). Science, 197, 557–561.

  • Boyer SN, Wazer DE and Band V . (1996). Cancer Res., 56, 4620–4624.

  • Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ and Kouzarides T . (1998). Nature, 291, 597–601.

    Article  CAS  Google Scholar 

  • Cairney M and Campo MS . (1995). Carcinogenesis, 16, 1997–2001.

    Article  CAS  Google Scholar 

  • Campo MS, O'Neil BW, Barron RJ and Jarrett WF . (1994). Carcinogenesis, 15, 1597–1601.

    Article  CAS  Google Scholar 

  • Carrano AC, Eytan E, Hershko A and Pagano M . (1999). Nat. Cell Biol., 1, 193–199.

  • Casagrande F and Darbon JM . (2001). Biochem. Pharmacol., 61, 1205–1215.

  • Casson AG, Wilson SM, McCart JA, O'Malley FP, Ozcelik H, Tsao MS and Chambers AF . (1997). Int. J. Cancer, 72, 739–745.

    Article  CAS  Google Scholar 

  • Chang F, Syrjanen S, Shen Q, Ji H and Syrjanen K . (1990). Int. J. Cancer, 45, 21–25.

    Article  CAS  Google Scholar 

  • Choi JA, Kim JY, Lee JY, Kang CM, Kwon HJ, Yoo YD, Kim TW, Lee YS and Lee SJ . (2001). Int. J. Cancer, 19, 837–844.

  • Conrad M, Bubb VJ and Schlegel R . (1993). J. Virol., 67, 6170–6178.

  • Cooper K, Taylor L and Govind S . (1995). J. Pathol., 175, 273–277.

    Article  CAS  Google Scholar 

  • Davies SP, Reddy H, Caivano M and Cohen P . (2000). Biochem. J., 351, 95–105.

    Article  CAS  Google Scholar 

  • De Villiers EM, Lavergne D, Chang F, Syrjanen K, Tosi P, Cintorino M, Santopietro R and Syrjanen S . (1999). Int. J. Cancer, 81, 225–228.

  • Dell G and Gaston K . (2001). Cell. Mol. Life Sci., 58, 1923–1942.

  • Fazal F, Rahman A, Greensill J, Ainley K, Hadi SM and Parish JH . (1990). Carcinogenesis, 11, 2005–2008.

    Article  CAS  Google Scholar 

  • Funk JO, Waga S, Harry JB, Espling E, Stillman B and Galloway DA . (1997). Genes Dev., 11, 2090–2100.

  • Galiana C, Lozano JC, Bancel B, Nakazawa H and Yamasaki H . (1995). Mol. Carcinog., 14, 286–293.

    Article  CAS  Google Scholar 

  • Galpin OP, Whitaker CJ, Whitaker RH and Kassab JY . (1990). Br. J. Cancer, 61, 737–740.

  • Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH, Wu L, Zahurak ML, David RW, Viglione M, Symer DE, Shah KV and Sidransky D . (2000). J. Nat. Cancer Inst., 92, 709–720.

  • Hara T, Kamura T, Nakayama K, Oshikawa K, Hatakeyama S and Nakayama K-I . (2001). J. Biol. Chem., 276, 48937–48943.

    Article  CAS  Google Scholar 

  • Hawley-Nelson P, Vousden KH, Hubbert NL, Lowy DR and Schiller JT . (1989). EMBO J., 8, 3905–3910.

  • Hirayama T . (1979). Nutr. Cancer, 1, 67–81.

  • Hirono I, Ogino H, Fujimoto M, Yamada K, Yoshida Y, Ikagawa M and Okumura M . (1987). J. Natl. Cancer Inst., 79, 1143–1149.

  • Ishidate Jr M, Harnois MC and Sofuni T . (1988). Mutat. Res., 195, 151–213.

  • Iwashita K, Kobori M, Yamaki K and Tsushida T . (2000). Biosci. Biotechnol. Biochem., 64, 1813–1820.

  • Jackson ME and Campo MS . (1995). DNA Tumour Viruses: Oncogenic Mechanisms. Barbanti-Brodano G (ed). Plenum Press: New York.

    Google Scholar 

  • Jackson ME, Pennie WD, McCaffery RE, Smith KT, Grindlay GJ and Campo MS . (1991). Mol. Carcinog., 4, 382–387.

    Article  CAS  Google Scholar 

  • Jones DL, Alani RM and Munger K . (1997a). Genes Dev., 11, 2102–2111.

  • Jones DL, Thompson DA and Munger K . (1997b). Virology, 239, 97–107.

    Article  CAS  Google Scholar 

  • Liang Y, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K, Lee J-H, Ciarallo S, Catzavelos C, Beniston R, Franssen E and Slingerland JM . (2002). Nat. Med., 10, 1163–1180.

  • Lloyd RV, Erickson LA, Jin L, Kulig E, Qian X, Cheville JC and Scheithauer BW . (1999). Am. J. Pathol., 154, 313–323.

  • Malek NP, Sundberg H, McGrew S, Nakayama K, Kyriakidis TR and Roberts JM . (2001). Nature, 413, 323–327.

    Article  CAS  Google Scholar 

  • Mantovani F and Banks L . (2001). Oncogene, 20, 7874–7887.

    Article  CAS  Google Scholar 

  • Marliere CA, Wathern P, Freitas RN, Castro MCFM and Galvao MAM . (2000). Bracken Fern: Toxicity, Biology and Control. Taylor JA, Smith RT (eds). The International Braekeu Group, Aberystwyth, Dyfed, Wales, pp. 144–149.

    Google Scholar 

  • Martin LG, Demers W and Galloway DA . (1998). J. Virol., 72, 975–985.

  • Matoba M, Saito E, Saito K, Koyama K, Natori S, Matsushima T and Takimoto M . (1987). Mutagenesis, 2, 419–423.

    Article  CAS  Google Scholar 

  • Munger K, Basile JR, Duensing S, Eichten A, Gonzalez SL, Grace M and Zacny VL . (2001). Oncogene, 20, 7888–7898.

    Article  Google Scholar 

  • Nakayama K-I, Hatakeyama S and Nakayama K . (2001). Biochem. Biophys. Res. Comm., 282, 853–860.

  • Nakayasu M, Sakamoto H, Terada M, Nagao M and Sugimura T . (1986). Mutat. Res., 174, 79–83.

  • Oelze I, Kartenbeck J, Crusius K and Alonso A . (1995). J. Virol., 69, 4489–4494.

  • Pennie WD and Campo MS . (1992). Virology, 190, 861–865.

    Article  CAS  Google Scholar 

  • Plaumann B, Fritsche M, Rimpler H, Brandner G and Hess RD . (1996). Oncogene, 13, 1605–1614.

  • Potter DM and Baird MS . (2000). Br. J. Cancer, 83, 914–920.

  • Reinstein E, Scheffner M, Oren M, Ciechanover A and Schwartz A . (2000). Oncogene, 19, 5944–5950.

    Article  CAS  Google Scholar 

  • Rong Y, Yang EB, Zhang K and Mack P . (2000). Anticancer Res., 20, 4339–4345.

  • Sano T, Masuda N, Oyama T and Nakajima T . (2002). Pathol. Int., 52, 375–383.

  • Sherr CJ and Roberts JM . (1999). Genes Dev., 13, 1501–1512.

  • Sorsdahl K, Casson AG, Troster M, Van Mayel D, Inculet R and Chambers AF . (1994). Cancer Detect. Prev., 18, 179–185.

  • Straight SW, Herman B and McCance DJ . (1995). J. Virol., 69, 3185–3192.

  • Suzuk L, Noffsinger AE, Hui YZ and Fenoglio-Preiser CM . (1996). Cancer, 78, 704–710.

    Article  CAS  Google Scholar 

  • Suzuki S, Takada T, Sugawara Y, Muto T and Kominami R . (1991). Jpn. J. Cancer Res., 82, 1061–1064.

  • Syrjanen KJ . (2002). J. Clin. Pathol., 55, 721–728.

  • Togawa K, Jaskiewicz K, Takahashi H, Meltzer SJ and Rustgi AK . (1994). Gastroenterology, 107, 128–136.

    Article  CAS  Google Scholar 

  • Vance KW, Campo MS and Morgan IM . (1999). J. Biol. Chem., 274, 27839–27844.

    Article  CAS  Google Scholar 

  • Villalobos-Salazar J, Mora J, Meneses A and Pashov B . (1995). “Bracken, an Environmental Issue.” Smith RT, Taylor A (eds). The International Braekeu Group, Aberystwyth, Dyfed, Wales, pp. 102–103.

    Google Scholar 

  • Yamashita N and Kawanishi S . (2000). Free Radic. Res., 33, 623–633.

  • Zehbe I, Rätsch A, Alunni-Fabbroni M, Burzlaff A, Bakos E, Dürst M, Wilander E and Tommasino M . (1999). Oncogene, 18, 2201–2211.

    Article  CAS  Google Scholar 

  • Zerfass-Thome K, Zwerschke W, Mannhardt B, Tindle R, Botz JW and Jansen-Durr P . (1996). Oncogene, 13, 2323–2330.

  • Zur Hausen H . (1996). Biochem. Biophys. Acta, 1288, F55–F78.

  • Zur Hausen H . (2000). J. Natl. Cancer Inst., 92, 690–698.

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Acknowledgements

We thank Dr G Sonenshein and Dr D Galloway for the kind gift of the pλ34-11 and pLXSN constructs, respectively. We are grateful to Dr I Morgan for critically reading the manuscript. This work is funded by WCRF International and Professor MS Campo is a Cancer Research UK Life Fellow.

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Correspondence to Maria Saveria Campo.

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Beniston, R., Campo, M. Quercetin elevates p27Kip1 and arrests both primary and HPV16 E6/E7 transformed human keratinocytes in G1. Oncogene 22, 5504–5514 (2003). https://doi.org/10.1038/sj.onc.1206848

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