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Tamoxifen induces p21WAF1 and p27KIP1 expression in estrogen receptor-negative lung cancer cells

Oncogene volume 18, pages 4269–4274 (1999)Cite this article

Abstract

Tamoxifen (Tam), besides its action as an anti-estrogen, also inhibits cell proliferation of estrogen receptor (ER)-negative cancer cells by an unknown mechanism. In this study, we used ER-negative lung cancer cells to clarify such ER-independent inhibitory effect of Tam. We found that Tam induced G1 growth arrest in these cells. However, our results indicated that the expression of G1 cyclins (including D1, 2, 3 and E) was not regulated by Tam in these lung cancer cells. Additionally, the protein levels of G1 acting cyclin-dependent kinases (CDKs), CDK2, 4 and 6, was unaltered in Tam-treated lung cancer cells with the exception of CDK2 expression in H322 cells which was attenuated by Tam in a cell line-specific manner. We next examined the effect of Tam on the expression of cyclin-dependent kinase inhibitors (CDKIs) and our results demonstrated that the expression of p21WAF1 and p27KIP1, but not p57KIP2, was strongly activated by Tam in these cells. The amounts of p21WAF1 and p27KIP1 co-immunoprecipitated with cyclin E were obviously increased after Tam treatment and reduced activity of cyclin E-associated kinases and accumulation of hypo-phosphorylated retinoblastoma (Rb) protein were clearly detected in Tam-incubated cells. No consentaneous induction of CDKIs was found when ER-negative lung cancer cells were incubated with cytotoxic drugs, cisplatin and etoposide, this indicates that enhancement of CDKI expression is not a non-specific effect of Tam. We also found that Tam may up-regulate p21WAF1 expression via transcription activation. Considered together, these results suggest that Tam-induced growth inhibition in ER-negative lung cancer cells is associated with induction of p21WAF1 and p27KIP1.

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References

  • Amon A, Tyers M, Futcher B and Nasmyth D. . 1993 Cell 74: 993–1007.

  • Bates S and Vousden KH. . 1996 Curr. Opin. Genet. Dev. 6: 12–18.

  • Bennett W, El-Deiry WS, Rush WL, Guinee DG, Freedman AN, Caporaso NE, Welsh JA, Jones RT, Borkowski A, Travis WD, Fleming MV, Trastek V, Pairolero PC, Tazelaar HD, Midthun D, Jett JR, Liotta LA and Harris CC. . 1998 Clin. Cancer Res. 4: 1499–1506.

  • Cabot MC, Giuliano AE, Volner A and Han TY. . 1996 FEBS Lett. 394: 129–131.

  • Caputi M, Esposito V, Baldi A, Luca AD, Dean C, Signoriello G, Baldi F and Giodano A. . 1998 Am. J. Respir. Cell Mol. Biol. 18: 213–217.

  • Chiba I, Takahashi T, Nau MM, D'Amico D, Curiel DT, Mitsudomi T, Bucchagen DL, Carbone D, Piantadosi S, Koga H, Reissman PT, Slamon DJ, Holmes EC and Minna JD. . 1990 Oncogene 5: 1603–1610.

  • Couldwell WT, Weiss MH, DeGiorgia CM, Weiner LP, Hinton DR, Ehresmann GR, Conti PS and Apuzzo ML. . 1993 Neurosurgery 32: 485–489.

  • Cover CM, Hsieh SJ, Tran SH, Hallden G, Kim GS, Bjeldanes LF and Firestone GL. . 1998 J. Biol. Chem. 273: 3838–3847.

  • Croxtall JD, Emmas C, White JO, Choudhary Q and Flower RJ. . 1994 Biochem. Pharmacol. 47: 197–202.

  • DelPrete SA, Maurer LH, O'Donnel J, Forcier JR and LeMarbre P. . 1984 Cancer Treat. Rep. 68: 1403–1405.

  • El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW and Vogelstein B. . 1993 Cell 75: 817–825.

  • Enmark E, Pelto-Huikko M, Grandien K, Lagercrantz S, Lagercrantz J, Fried G, Nordenskjold M and Gustafsson J. . 1997 J. Clin. Endocrinol. Metab. 82: 4258–4265.

  • Furr BJA and Jordan VC. . 1984 Pharmacol. Ther. 25: 127–205.

  • Guadagno TM and Newport JW. . 1996 Cell 84: 73–82.

  • Henderson BE, Ross RK and Pike MC. . 1992 Science 259: 633–638.

  • Hengst L and Reed SI. . 1996 Science 2271: 1861–1864.

  • Hirai H, Roussel MF, Kato JY, Ashmun RA and Sherr CJ. . 1995 Mol. Cell. Biol. 15: 2672–2681.

  • Hung WC, Chai CY, Huang JS and Chuang LY. . 1996a Hum. Pathol. 27: 1324–1328.

  • Hung WC, Huang JS and Chuang LY. . 1996b Biochem. Biophys. Res. Commun. 220: 719–723.

  • Jordan VC and Murphy CS. . 1990 Endocrin. Rev. 11: 578–610.

  • Jordan VC, Lababidi MK and Fakhey SL. . 1991 J. Natl. Cancer Inst. 83: 492–496.

  • Jordan VC. . 1994 Breast Cancer Res. Treat. 31: 41–52.

  • Knabbe C, Lippman ME, Wakefield LM, Flanders KC, Kasid A, Derynck R and Dickson RB. . 1987 Cell 48: 417–428.

  • Kiss Z. . 1994 FEBS Lett. 355: 173–177.

  • Komiya T, Hosono Y, Hirashima T, Masuda N, Yasumitsu T, Nakagawa K, Kikui M, Ohno A, Fukuoka M and Kawase I. . 1997 Clin. Cancer Res. 3: 1831–1835.

  • Kuiper GGJM, Enmark E, Pelto-Huikko M, Nisson S and Gustafsson JA. . 1996 Proc. Natl. Acad. Sci. USA 93: 5925–5930.

  • Kyle E, Neckers L, Takimoto C, Curt G and Bergan RC. . 1997 Mol. Pharmacol. 51: 193–200.

  • Lew DJ and Kornbluth S. . 1996 Curr. Opin. Cell Biol. 8: 795–804.

  • Liu M, Lee MH, Cohen M, Bommakanti M and Freedman LP. . 1996 Genes Dev. 10: 142–153.

  • McClay E, McClay ME, Jones J, Winski P, Christen R, Howell S and Hall PA. . 1997 Cancer 79: 1037–1043.

  • Minami S, Ohtani-Fujita N, Igata E, Tamaki T and Sakai T. . 1997 FEBS Lett. 411: 1–6.

  • Mitsudomi T, Steinberg SM, Nau MM, Carbone D, D'Amico D, Borner S, Oie HK, Linnoila I, Mulshine JL, Minna JD and Gazdar AF. . 1992 Oncogene 7: 171–180.

  • Mosmann T. . 1983 J. Immunol. Meth. 65: 55–63.

  • O'Brian CA, Liskkamp RM, Soloman DH and Weinstein IB. . 1986 J. Natl. Cancer Inst. 76: 1243–1246.

  • Pagano M, Tam SW, Theoforas AM, Beer-Romero P, Sal GD, Chau V, Yew PR, Draetta GF and Rolfe M. . 1995 Science 269: 682–685.

  • Pines J. . 1993 Trends Biochem. Sci. 18: 195–197.

  • Planas-Silva MD and Weinberg RA. . 1997 Mol. Cell. Biol. 17: 4059–4069.

  • Poluha W, Poulha DK, Chang B, Crosbie NE, Schonhoff CM, Kilpatrick DL and Ross AH. . 1996 Mol. Cell. Biol. 16: 1335–1341.

  • Polyak K, Lee MH, Erdjument BH, Koff A, Roberts JM, Tempst P and Massague J. . 1994 Cell 78: 59–66.

  • Robinson EK, Grau AM, Evans DB, Smid CM, Chiao PJ, Abbruzzese JL and Grimm EA. . 1998 Ann. Surg. Oncol. 5: 342–349.

  • Rohlff C, Blagoskonny MV, Kyle E, Kesari A, Kim IY, Zelner DJ, Hakim F, Trepel J and Bergan RC. . 1998 Prostate 37: 51–59.

  • Rowlands MG, Parr IB, McCaque R, Jarman M and Goddard PM. . 1990 Biochem. Pharmacol. 40: 283–289.

  • Serrano M, Hannon GJ and Beach D. . 1993 Nature 366: 704–707.

  • Sutherland RL, Reddel RR and Green MD. . 1983 Eur. J. Clin. Oncol. 19: 307–318.

  • Takahashi T, Nau MM, Chiba I, Birrer MJ, Rosenberg RK, Vinocour M, Levitt M, Pass H, Gazdar AF and Minna JD. . 1989 Science 246: 491–494.

  • Teixeira C and Pratt MAC. . 1997 Mol. Endocrinol. 11: 1191–1202.

  • Tremblay GB, Tremblay A, Copeland NG, Gilbert DJ, Jenkins NA, Labrie F and Giguere V. . 1997 Endocrinol. 11: 353–365.

  • Trump DL, Smith DC, Ellis PG, Rogers MP, Schold SC, Winer EP, Panella TJ, Jordan VC and Fine RL. . 1992 J. Natl. Cancer Inst. 84: 1811–1816.

  • van den Heuvel and Harlow E. . 1993 Science 262: 2050–2054.

  • Yatabe Y, Masuda A, Koshikawa T, Nakamura S, Kuroishi T, Osada H, Takahashi T, Mitsudomi T and Takahashi T. . 1998 Cancer Res. 58: 1042–1047.

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Acknowledgements

We thank Dr K Fang for providing the lung cancer cell lines and Dr B Vogelstein for providing the WWP-luc plasmids.

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  1. Graduate Institute of Medicine, Kaohsiung Medical College, No 100 Shih Chuan 1st Road, Kaohsiung, 807, Taiwan, Republic of China

    Te-Hsiu Lee

  2. Department of Biochemistry, Kaohsiung Medical College, No 100 Shih Chuan 1st Road, Kaohsiung, 807, Taiwan, Republic of China

    Lea-Yea Chuang

  3. School of Technology for Medical Sciences, Kaohsiung Medical College, No 100 Shih Chuan 1st Road, Kaohsiung, 807, Taiwan, Republic of China

    Wen-Chun Hung

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Lee, TH., Chuang, LY. & Hung, WC. Tamoxifen induces p21WAF1 and p27KIP1 expression in estrogen receptor-negative lung cancer cells. Oncogene 18, 4269–4274 (1999). https://doi.org/10.1038/sj.onc.1202755

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