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Sulfasalazine induces apoptosis of HBx-expressing cells in an NF-κB-independent manner

Abstract

The Hepatitis B virus (HBV) is a causative agent of acute chronic hepatitis, cirrhosis, and hepatocarcinoma. The Hepatitis B virus X protein (HBx) has pleiotypic functions in the regulation of proliferation and apoptosis. It has been suggested that the anti-inflammatory drug sulfasalazine, which is commonly used to treat rheumatoid arthritis and inflammatory bowel disease, inhibits nuclear factor NF-κB and induces cell death in HBx-expressing liver cells. In this study, we demonstrate that sulfasalazine induces cell death via apoptosis in HBx-expressing liver cells, as evidenced by characteristic changes in nuclear morphology, cleavage of poly (ADP-ribose) polymerase (PARP), caspase-3 and caspase-9, and activation of caspase-3. We also demonstrate that inhibition of NF-κB by siRNA fails to induce apoptosis of HBx-expressing liver cells, indicating that sulfasalazine modulates apoptosis of HBx-expressing cells in an NF-κB-independent manner.

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References

  1. 1.

    R.P. Beasley, L.Y. Hwang, C.C. Lin, C.S. Chien, Lancet 2, 1129–1133 (1981)

  2. 2.

    H.S. Chen, S. Kaneko, R. Girones, R.W. Anderson, W.E. Hornbuckle, B.C. Tennant, P.J. Cote, J.L. Gerin, R.H. Purcell, R.H. Miller, J. Virol. 67, 1218–1226 (1993)

  3. 3.

    H. Kim, H. Lee, Y. Yun, J. Biol. Chem. 273, 381–385 (1998)

  4. 4.

    W.L. Shih, M.L. Kuo, S.E. Chuang, A.L. Cheng, S.L. Doong, J. Biol. Chem. 275, 25858–25864 (2000)

  5. 5.

    J. Benn, R.J. Schneider, Proc. Natl Acad. Sci. USA 92, 11215–11219 (1995)

  6. 6.

    K. Koike, K. Moriya, H. Yotsuyanagi, S. Iino, K. Kurokawa, J. Clin. Invest. 94, 44–49 (1994)

  7. 7.

    H.F. Maguire, J.P. Hoeffler, A. Siddiqui, Science 252, 842–844 (1991)

  8. 8.

    Y. Mahe, N. Mukaida, K. Kuno, M. Akiyama, N. Ikeda, K. Matsushima, S. Murakami, J. Biol. Chem. 266, 13759–13763 (1991)

  9. 9.

    P. Chirillo, M. Falco, P.L. Puri, M. Artini, C. Balsano, M. Levrero, G. Natoli, J. Virol. 70, 641–646 (1996)

  10. 10.

    J. Benn, F. Su, M. Doria, R.J. Schneider, J. Virol. 70, 4978–4985 (1996)

  11. 11.

    M. Doria, N. Klein, R. Lucito, R.J. Schneider, EMBO J. 14, 4747–4757 (1995)

  12. 12.

    F.V. Chisari, Curr. Top. Microbiol. Immunol. 206, 149–173 (1996)

  13. 13.

    C. Wahl, S. Liptay, G. Adler, R.M. Schmid, J. Clin. Invest. 101, 1163–1174 (1998)

  14. 14.

    C.D. Brooks, J. Rheumatol. 28, 845–853 (2001)

  15. 15.

    M. Hermisson, M. Weller, Cell Death Differ. 10, 1078–1089 (2003)

  16. 16.

    O.I. Aruoma, M. Wasil, B. Halliwell, B.M. Hoey, J. Butler, Biochem. Pharmacol. 36, 3739–3742 (1987)

  17. 17.

    S. Tornhamre, C. Edenius, G. Smedegard, B. Sjoquist, J.A. Lindgren, Eur. J. Pharmacol. 169, 225–234 (1989)

  18. 18.

    T. Akahoshi, R. Namai, N. Sekiyama, S. Tanaka, S. Hosaka, H. Kondo, J. Leukoc. Biol. 62, 817–826 (1997)

  19. 19.

    S. Liptay, M. Bachem, G. Hacker, G. Adler, K.M. Debatin, R.M. Schmid, Br. J. Pharmacol. 128, 1361–1369 (1999)

  20. 20.

    S. Liptay, S. Fulda, M. Schanbacher, S. Bourteele, K.F. Ferri, G. Kroemer, G. Adler, K.M. Debatin, R.M. Schmid, Br. J. Pharmacol. 137, 608–620 (2002)

  21. 21.

    C. Yun, H.R. Um, Y.H. Jin, J.H. Wang, M.O. Lee, S. Park, J.H. Lee, H. Cho, Cancer Lett. 184, 97–104 (2002)

  22. 22.

    C. Yun, J.H. Lee, H. Park, Y.M. Jin, S. Park, K. Park, H. Cho, Oncogene 19, 5163–5172 (2000)

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Acknowledgments

We thank Dr. Y. Yun for providing the anti-HBx antibody. This work was conducted in whole or in part with Grant M10503010002 (Y.K.) and M10534040001 (Y.K.) from the Korea Research Foundation and with research grants from the Inje University Research Initiative and First Program.

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Correspondence to Yeon-Soo Kim.

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Lee, Y., Kang, M., Hwang, J. et al. Sulfasalazine induces apoptosis of HBx-expressing cells in an NF-κB-independent manner. Virus Genes 40, 37–43 (2010). https://doi.org/10.1007/s11262-009-0416-4

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Keywords

  • HBx
  • Apoptosis
  • Sulfasalazine
  • NF-κB