Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Analysis of FasL and TRAIL induced apoptosis pathways in glioma cells

Abstract

FasL and TNF-related apoptosis-inducing ligand (TRAIL) belong to a subgroup of the TNF superfamily which induce apoptosis by binding to their death domain containing receptors. In the present study we have utilized a panel of seven cell lines derived from human malignant gliomas to characterize molecular pathways through which FasL and TRAIL induce apoptosis in sensitive glioma cells and the mechanisms of resistance in cell lines which survive the death stimuli. Our findings indicate that FADD and Caspase-8 are essential for FasL and TRAIL mediated apoptosis in glioma cells. One sensitive cell line (D270) can be protected from FasL and TRAIL induced death by anti-apoptotic Bcl-2 family members while another (D645) cannot, implying that these lines may represent glioma examples of type II and type I cells respectively. For the first time we demonstrate resistance to FasL but not to TRAIL within the one glioma cell line. Furthermore, we report distinct mechanisms of resistance within different glioma lines, including downregulation of Caspase-8 in U373MG. Cycloheximide sensitized four of the resistant cell lines suggesting the presence of labile inhibitors. None of the known apoptosis inhibitors examined accounted for the observed resistance, suggesting novel inhibitors may exist in glioma cells.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 6
Figure 3
Figure 4
Figure 5
Figure 7

Similar content being viewed by others

Abbreviations

CHX:

cycloheximide

DD:

death domain

DED:

death effector domain

DISC:

death-inducing signaling complex

PBS:

phosphate buffered saline

TNF:

tumor necrosis factor

TRAIL:

TNF-related apoptosis-inducing ligand

References

  • Bai C, Connolly B, Metzker ML, Hilliard CA, Liu X, Sandig V, Soderman A, Galloway SM, Liu Q, Austin CP, Caskey CT . 2000 Proc. Natl. Acad. Sci. USA 97: 1230–1235

  • Bigner D, Bigner S, Ponten J, Westermark B, Mahaley M, Ruoslahti E, Herschman H, Eng L, Wikstrand C . 1981 J. Neuropathol. Exp. Neurol. 40: 201–229

  • Chomczynski P, Sacchi N . 1987 Anal. Biochem. 162: 156–159

  • Condorelli G, Vigliotta G, Cafieri A, Trencia A, Andolo P, Oriente F, Miele C, Caruso M, Formisano P, Beguinot F . 1999 Oncogene 18: 4409–4415

  • Coultas L, Strasser A . 2000 Apoptosis 5: 491–507

  • de Leeuw WJ, Slagboom PE, Vijg J . 1989 Nucleic Acids Res. 17: 10137–10138

  • Deveraux Q, Takahashi R, Salvesen G, Reed J . 1997 Nature 388: 300–304

  • Griffith TS, Chin WA, Jackson GC, Lynch DH, Kubin MZ . 1998 J. Immunol. 161: 2833–2840

  • Gross A, McDonnell J, Korsmeyer S . 1999 Genes Dev. 13: 1899–1911

  • Hao C, Beguinot F, Condorelli G, Trencia A, Van Meir EG, Yong VW, Parney IF, Roa WH, Petruk KC . 2001 Cancer Res. 61: 1162–1170

  • Hawkins CJ, Uren AG, Hacker G, Medcalf RL, Vaux DL . 1996 Proc. Natl. Acad. Sci. USA 93: 13786–13790

  • Hawkins CJ, Wang SL, Hay BA . 1999 Proc. Natl. Acad. Sci. USA 96: 2885–2890

  • Hinz S, Trauzold A, Boenicke L, Sandberg C, Beckmann S, Bayer E, Walczak H, Kalthoff H, Ungefroren H . 2000 Oncogene 19: 5477–5486

  • Hitoshi Y, Lorens J, Kitada SI, Fisher J, LaBarge M, Ring HZ, Francke U, Reed JC, Kinoshita S, Nolan GP . 1998 Immunity 8: 461–471

  • Hopkins-Donaldson S, Bodmer JL, Bourloud KB, Brognara CB, Tschopp J, Gross N . 2000 Cancer Res. 60: 4315–4319

  • Hosli P, Sappino A, de Tribolet N, Dietrich P . 1998 Ann. Oncol. 9: 589–600

  • Huang D, Hahne M, Schroeter M, Frei K, Fontana A, Villunger A, Newton K, Tschopp J, Strasser A . 1999 Proc. Natl. Acad. Sci. USA 96: 14871–14876

  • Irmler M, Thome M, Hahne M, Schneider P, Hofmann B, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J . 1997 Nature 388: 190–195

  • Jenkins M, Keir M, McCune JM . 2000 J. Biol. Chem. 275: 7988–7993

  • Juo P, Kuo CJ, Yuan J, Blenis J . 1998 Curr. Biol. 8: 1001–1008

  • Juo P, Woo MS, Kuo CJ, Signorelli P, Biemann HP, Hannun YA, Blenis J . 1999 Cell Growth Differ. 10: 797–804

  • Keane MM, Ettenberg SA, Nau MM, Russell EK, Lipkowitz S . 1999 Cancer Res. 59: 734–741

  • Kim EJ, Suliman A, Lam A, Srivastava RK . 2001 Int. J. Oncol. 18: 187–194

  • Kim K, Fisher MJ, Xu SQ, el-Deiry WS . 2000 Clin. Cancer Res. 6: 335–346

  • Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME . 1995 EMBO J. 14: 5579–5588

  • Kitsberg D, Formstecher E, Fauquet M, Kubes M, Cordier J, Canton B, Pan G, Rolli M, Glowinski J, Chneiweiss H . 1999 J. Neurosci. 19: 8244–8251

  • Leverkus M, Neumann M, Mengling T, Rauch CT, Brocker EB, Krammer PH, Walczak H . 2000 Cancer Res. 60: 553–559

  • Li H, Zhu H, Xu C, Yuan J . 1998 Cell 94: 491–501

  • Luo X, Budihardjo I, Zou H, Slaughter C, Wang X . 1998 Cell 94: 481–490

  • Miller TM, Moulder KL, Knudson CM, Creedon DJ, Deshmukh M, Korsmeyer SJ, Johnson EM . 1997 J. Cell Biol. 139: 205–217

  • Miura M, Zhu H, Rotello R, Hartweig EA, Yuan J . 1993 Cell 75: 653–660

  • Myc A, Arscott PL, Bretz JD, Thompson NW, Baker JR . 1999 Endocrinol. 140: 5431–5434

  • Newton K, Harris AW, Bath ML, Smith KG, Strasser A . 1998 EMBO J. 17: 706–718

  • Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C . 1991 J. Immunol. Meth. 139: 271–279

  • Perlman H, Pagliari LJ, Georganas C, Mano T, Walsh K, Pope RM . 1999 J. Exp. Med. 190: 1679–1688

  • Pitti RM, Marsters SA, Lawrence DA, Roy M, Kischkel FC, Dowd P, Huang A, Donahue CJ, Sherwood SW, Baldwin DT, Godowski PJ, Wood WI, Gurney AL, Hillan KJ, Cohen RL, Goddard AD, Botstein D, Ashkenazi A . 1998 Nature 396: 699–703

  • Reed J . 1999 J. Clin. Oncol. 17: 2941–2953

  • Reed JC . 2000 Am. J. Pathol. 157: 1415–1430

  • Rieger J, Naumann U, Glaser T, Ashkenazi A, Weller M . 1998 FEBS Lett. 427: 124–128

  • Roth W, Isenmann S, Nakamura M, Platten M, Wick W, Kleihues P, Bahr M, Ohgaki H, Ashkenazi A, Weller M . 2001 Cancer Res. 61: 2759–2765

  • Roth W, Weller M . 1999 Cell. Mol. Life Sci. 56: 481–506

  • Sambrook J, Fritsch E, Maniatis T . 1989 Molecular Cloning: A Laboratory Manual 2nd edn Cold Spring Harbor Laboratory Press

    Google Scholar 

  • Sato T, Irie S, Kitada S, Reed JC . 1995 Science 268: 411–415

  • Scaffidi C, Fulda S, Srinivasen A, Friesen C, Li F, Tomaselli K, Debatin K-M, Krammer P, Peter M . 1998 EMBO J. 17: 1675–1687

  • Scaffidi C, Schmitz I, Krammer P, Peter M . 1999a J. Biol. Chem. 274: 1541–1548

  • Scaffidi C, Schmitz I, Zha J, Korsmeyer SJ, Krammer PH, Peter ME . 1999b J. Biol. Chem. 274: 22532–22538

  • Schneider P, Holler N, Bodmer JL, Hahne M, Frei K, Fontana A, Tschopp J . 1998 J. Exp. Med. 187: 1205–1213

  • Shin M, Park W, Kim S, Kim H, Kang S, Song K, Park J, Dong S, Pi J, Oh R, Lee J, Yoo N, Lee S . 1999 Am. J. Pathol. 154: 1785–1791

  • Somia N, Schmitt M, Vetter D, Van Antwerp D, Heinemann S, Verma I . 1999 Proc. Natl. Acad. Sci. USA 96: 12667–12672

  • Sprick MR, Weigand MA, Rieser E, Rauc CT, Juo P, Blenis J, Krammer PH, Walczak H . 2000 Immunity 12: 599–609

  • Strasser A, Harris AW, Huang D, Krammer PH, Cory S . 1995 EMBO J. 14: 6136–6147

  • Teitz T, Wei T, Valentine MB, Vanin EF, Grenet J, Valentine VA, Behm FG, Look AT, Lahti JM, Kidd VJ . 2000 Nat. Med. 6: 529–535

  • Truneh A, Sharma S, Silverman C, Khandekar S, Reddy MP, Deen KC, McLaughlin MM, Srinivasula SM, Livi GP, Marshall LA, Alnemri ES, Williams WV, Doyle ML . 2000 J. Biol. Chem. 275: 23319–23325

  • Tschopp J, Irmler M, Thome M . 1998 Curr. Opin. Immunol. 10: 552–558

  • Wen J, Ramadevi N, Nguyen D, Perkins C, Worthington E, Bhalla K . 2000 Blood 96: 3900–3906

  • Wolf B, Green D . 1999 J. Biol. Chem. 274: 20049–20052

  • Wrone-Smith T, Izban KF, Ergin M, Cosar EF, Hsi ED, Alkan S . 2001 Exp. Hematol. 29: 572–581

  • Wu M, Das A, Tan Y, Zhu C, Cui T, Wong MC . 2000 J. Neurosci. Res. 61: 464–470

  • Yanagisawa J, Takahashi M, Kanki H, Yano-Yanagisawa H, Tazunoki T, Sawa E, Nishitoba T, Kamishohara M, Kobayashi E, Kataoka S, Sato T . 1997 J. Biol. Chem. 272: 8539–8545

  • Yu KY, Kwon B, Ni J, Zhai Y, Ebner R, Kwon BS . 1999 J. Biol. Chem. 274: 13733–13736

  • Zhang X, Franco A, Myers K, Gray C, Nguyen T, Hersey P . 1999 Cancer Res. 59: 2747–2753

  • Zhang XD, Franco AV, Nguyen T, Gray CP, Hersey P . 2000a J. Immunol. 164: 3961–3970

  • Zhang XJ, Yan J, Cuttle L, Endre Z, Gobe G . 2000b Biochem. Biophys. Res. Commun. 277: 487–493

  • Zou H, Li Y, Liu X, Wang X . 1999 J. Biol. Chem. 274: 11549–11556

Download references

Acknowledgements

The authors acknowledge the advice and generous donations of reagents from the following people: Drs David Vaux, David Huang, Andreas Strasser, Paul Ekert, Marcus Peter, Andriano Fontano, Darell Bigner, Mark Schmitt and also Janna Stickland for her help with the preparation of Figures. This study was funded by a James S McDonnell Foundation Program Grant and a National Health and Medical Research Council Project Grant.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christine J Hawkins.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Knight, M., Riffkin, C., Muscat, A. et al. Analysis of FasL and TRAIL induced apoptosis pathways in glioma cells. Oncogene 20, 5789–5798 (2001). https://doi.org/10.1038/sj.onc.1204810

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204810

Keywords

This article is cited by

Search

Quick links