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Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand

Nature Medicine volume 6, pages 564–567 (2000)Cite this article

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to induce apoptosis in various tumor cells but not in nontransformed, normal cells1,2,3. Preclinical studies in mice and nonhuman primates have shown that administration of TRAIL can induce apoptosis in human tumors, but that no cytotoxicity to normal organs or tissues is found3,4. The susceptibility of tumor cells to TRAIL and an apparent lack of activity in normal cells has lead to a proposal to use TRAIL in cancer therapy. Here, we assessed the sensitivity of hepatocytes from rat, mouse, rhesus monkey and human livers to TRAIL-induced apoptosis. TRAIL induced apoptosis in normal human hepatocytes in culture but not in hepatocytes isolated from the other species. Human hepatocytes showed characteristic features of apoptosis, including cytoplasmic shrinkage, the activation of caspases and DNA fragmentation. Apoptosis and cell death in human hepatocytes was massive and rapid, occurring in more than 60% of the cells exposed to TRAIL within 10 hours. These results indicate that there are species differences in sensitivity to TRAIL, and that substantial liver toxicity might result if TRAIL were used in human cancer therapy.

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Figure 1: a, rhTRAIL-induced cytotoxicity and apoptosis.
Figure 2: Activation of caspases in TRAIL-induced apoptosis in human hepatocytes.
Figure 3: RT–PCR analysis of the expression of TRAIL receptors in human liver tissue, human hepatocytes in culture, tumor cell line (HepG2), human fetal liver tissue (FT), and human fetal hepatocytes (FC).

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References

  1. Pitti, R.M. et al. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J. Biol. Chem. 271, 12687–12690 (1996).

    Article  CAS  Google Scholar 

  2. Wiley, S.R. et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3, 673–682 (1995).

    Article  CAS  Google Scholar 

  3. Walczak, H. et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nature Med. 5, 157 –163 (1999).

    Article  CAS  Google Scholar 

  4. Ashkenazi, A. et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J. Clin. Invest. 104, 155– 162 (1999).

    Article  CAS  Google Scholar 

  5. Li, P. et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91, 479–489 (1997).

    Article  CAS  Google Scholar 

  6. Germain, M. et al. Cleavage of automodified Poly(ADP-ribose) polymerase during apoptosis. Evidence for involvement of caspase-7. J. Biol. Chem. 274, 28379–28384 ( 1999).

    Article  CAS  Google Scholar 

  7. D'Amours, D., Germain, M., Orth, K., Dixit, V.M. & Poirier, G.G. Proteolysis of poly(ADP-ribose) polymerase by caspase 3: kinetics of cleavage of mono(ADP-ribosyl)ated and DNA-bound substrates . Radiat. Res. 150, 3–10 (1998).

    Article  CAS  Google Scholar 

  8. Tang, D. & Kidd, V.J. Cleavage of DFF-45/ICAD by multiple caspases is essential for its function during apoptosis. J. Biol. Chem. 273, 28549–28552 ( 1998).

    Article  CAS  Google Scholar 

  9. Pan, G. et al. The receptor for the cytotoxic ligand TRAIL. Science 276, 111–3 ( 1997).

    Article  CAS  Google Scholar 

  10. Walczak, H. et al. TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. Embo. J. 16, 5386–5397 ( 1997).

    Article  CAS  Google Scholar 

  11. Pan, G. et al. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 277, 815– 818 (1997).

    Article  CAS  Google Scholar 

  12. Sheridan, J.P. et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277, 818– 821 (1997).

    Article  CAS  Google Scholar 

  13. Degli-Esposti, M.A. et al. Cloning and characterization of TRAIL-R3, a novel member of the emerging TRAIL receptor family. J. Exp. Med. 186 , 1165–1170 (1997).

    Article  CAS  Google Scholar 

  14. Pan, G., Ni, J., Yu, G., Wei, Y.F. & Dixit, V.M. TRUNDD, a new member of the TRAIL receptor family that antagonizes TRAIL signalling. FEBS Lett. 424, 41–55 (1998).

    Article  CAS  Google Scholar 

  15. Fiers, W. Tumor necrosis factor. Characterization at the molecular, cellular and in vivo level. FEBS Lett. 285, 199– 212 (1991).

    Article  CAS  Google Scholar 

  16. Havell, E.A., Fiers, W. & North, R.J. The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity. J. Exp. Med. 167, 1067–1085 ( 1988).

    Article  CAS  Google Scholar 

  17. Tanaka, M., Suda, T., Yatomi, T., Nakamura, N. & Nagata, S. Lethal effect of recombinant human Fas ligand in mice pretreated with Propionibacterium acnes. J. Immunol. 158, 2303–2309 (1997).

    CAS  PubMed  Google Scholar 

  18. Ogasawara, J. et al. Lethal effect of the anti-Fas antibody in mice. Nature 364, 806–809 ( 1993); erratum 365(6446):568 ( 1993).

    Article  CAS  Google Scholar 

  19. Strom, S.C. et al. Use of human hepatocytes to study P450 gene induction. Meth. Enzymol. 272, 388–401 (1996).

    Article  CAS  Google Scholar 

  20. Strom, S.C., Dorko, K., Thompson, M.T., Pisarov, L.A. & Nussler, A.K. Ilots de Langerhans et Hepatocytes (eds. Franco, D., Boudjema, K. & Varet, B.) 195– 205 (Institut National de la Sante et de la Recherche Medicale, Paris, 1998).

    Google Scholar 

  21. Nussler, A.K. et al. Isolation and characterization of a human hepatic epithelial-like cell line (AKN-1) from a normal liver. In Vitro Cell Dev. Biol. Anim. 35, 190–197 ( 1999).

    Article  CAS  Google Scholar 

  22. Seol, D.W. & Billiar, T.R. A caspase-9 variant missing the catalytic site is an endogenous inhibitor of apoptosis. J. Biol. Chem. 274, 2072–2076 ( 1999).

    Article  CAS  Google Scholar 

  23. Bohlinger, I. et al. DNA fragmentation in mouse organs during endotoxic shock. Am. J. Pathol. 149, 1381–1393 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Kothny-Wilkes, G. et al. Interleukin-1 protects transformed keratinocytes from tumor necrosis factor-related apoptosis-inducing ligand. J. Biol. Chem. 273, 29247–53 ( 1998).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by National Institutes of Health grant NO1-DK-92310 to S.C.S and by RO1-GM-50441 to T.R.B.

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Authors and Affiliations

  1. Department of Pathology, School of Medicine, 200 Lothrop St. BST S-450, University of Pittsburgh, Pittsburgh , 15261, Pennsylvania, USA

    Minji Jo, Tae-Hyoung Kim, James E. Esplen, Kenneth Dorko & Stephen C. Strom

  2. Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, 15261 , Pennsylvania, USA

    Dai-Wu Seol & Timothy R. Billiar

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  1. Minji Jo
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Correspondence to Stephen C. Strom.

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Jo, M., Kim, TH., Seol, DW. et al. Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nat Med 6, 564–567 (2000). https://doi.org/10.1038/75045

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