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
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
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
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
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
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
Corresponding author
Rights 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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204810
Keywords
This article is cited by
-
The fungal metabolite chaetocin is a sensitizer for pro-apoptotic therapies in glioblastoma
Cell Death & Disease (2019)
-
Inhibition of Notch1 signaling overcomes resistance to the death ligand Trail by specificity protein 1-dependent upregulation of death receptor 5
Cell Death & Disease (2015)
-
The ER stress inducer DMC enhances TRAIL-induced apoptosis in glioblastoma
SpringerPlus (2014)
-
RETRACTED ARTICLE: A single chain (scFv425):sTRAIL fusion protein with specificity for the EGF receptor is effective in vitro but not in an in vivo brain tumor animal model
Journal of Neuro-Oncology (2013)
-
Cytokine networks in glioma
Neurosurgical Review (2011)