Abstract
Caspase-8 plays an essential role in apoptosis triggered by death receptors. Through the cleavage of Bid, a proapoptotic Bcl-2 member, it further activates the mitochondrial cytochrome c/Apaf-1 pathway. Because caspase-8 can be processed also by anticancer drugs independently of death receptors, we investigated its exact role and order in the caspase cascade. We show that in Jurkat cells either deficient for caspase-8 or overexpressing its inhibitor c-FLIP apoptosis mediated by CD95, but not by anticancer drugs was inhibited. In the absence of active caspase-8, anticancer drugs still induced the processing of caspase-9, -3 and Bid, indicating that Bid cleavage does not require caspase-8. Overexpression of Bcl-xL prevented the processing of caspase-8 as well as caspase-9, -6 and Bid in response to drugs, but was less effective in CD95-induced apoptosis. Similar responses were observed by overexpression of a dominant-negative caspase-9 mutant. To further determine the order of caspase-8 activation, we employed MCF7 cells lacking caspase-3. In contrast to caspase-9 that was cleaved in these cells, anticancer drugs induced caspase-8 activation only in caspase-3 transfected MCF7 cells. Thus, our data indicate that, unlike its proximal role in receptor signaling, in the mitochondrial pathway caspase-8 rather functions as an amplifying executioner caspase.
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References
Adams JM and Cory S. . 1998 Science 281: 1322–1326.
Bantel H, Engels IH, Voelter W, Schulze-Osthoff K and Wesselborg S. . 1999 Cancer Res. 59: 2083–2090.
Belka C, Marini P, Lepple-Wienhues A, Budach W, Jekle A, Los M, Lang F, Schulze-Osthoff K, Gulbins E and Bamberg M. . 1999 Oncogene 18: 4983–4992.
Chinnaiyan AM, O'Rourke K, Lane BR and Dixit VM. . 1997 Science 275: 1122–1126.
Cohen GM. . 1997 Biochem. J. 326: 1–16.
Cryns V and Yuan J. . 1998 Genes Dev. 12: 1551–1570.
Day CL, Dupont C, Lackmann M, Vaux DL and Hinds MG. . 1999 Cell Death Differ. 6: 1125–1132.
Dhein J, Walczak H, Bäumler C, Debatin KM and Krammer PH. . (1995) Nature 373: 438–441.
Eischen CM, Kottke TJ, Martins LM, Basi GS, Tung JS, Earnshaw WC, Leibson PJ and Kaufmann SH. . 1997 Blood 90: 935–943.
Fearnhead HO, Rodriguez J, Govek E-E, Guo W, Kobayashi R, Hannon G and Lazebnik, YA. . 1998 Proc. Natl. Acad. Sci. USA 95: 13664–13669.
Ferrari D, Stepczynska A, Los M, Wesselborg S and Schulze-Osthoff K. . 1998 J. Exp. Med. 188: 979–984.
Friesen C, Herr I, Krammer PH and Debatin KM. . 1996 Nat. Med. 2: 574–577.
Fulda S, Sieverts H, Friesen C, Herr I and Debatin KM. . 1997a Cancer Res. 57: 3823–3829.
Fulda S, Friesen C, Los M, Scaffidi C, Mier W, Benedict M, Nunez G, Krammer PH, Peter ME and Debatin KM. . 1997b Cancer Res. 57: 4956–4964.
Fulda S, Susin SA, Kroemer G and Debatin KM. . 1998 Cancer Res. 58: 4453–4460.
Gamen S, Anel A, Lasierra P, Alava MA, Martinez Lorenzo MJ, Pineiro A and Naval J. . 1997 FEBS Lett. 417: 360–364.
Goltsev YV, Kovalenko AV, Arnold E, Varfolomeev EE, Brodianskii VM and Wallach D. . 1997 J. Biol. Chem. 272: 19641–19644.
Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, Elia A, de la Pompa JL, Kagi D, Khoo W, Potter J, Yoshida R, Kaufman SA, Lowe SW, Penninger JM and Mak, TW. . 1998 Cell 94: 339–352.
Han J, Wallen HD, Nunez G and White E. . 1998 Mol. Cell. Biol. 18: 6052–6062.
Herr I, Wilhelm D, Bohler T, Angel P and Debatin KM. . 1998 EMBO J. 16: 6200–6208.
Hu S, Vincenz C, Ni J, Gent, R and Dixit VM. . 1997 J. Biol. Chem. 272: 17255–17257.
Hu Y, Benedict MA, Wu D, Inohara N and Nunez G. . 1998 Proc. Natl. Acad. Sci. USA 95: 4386–4391.
Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodme JL, Schroeter M, Burns K, Mattmann C, Rimoldi D, French LE and Tschopp J. . 1997 Nature 388: 190–195.
Jänicke RU, Sprengart ML, Wati MR and Porter AG. . 1998 J. Biol. Chem. 273: 9357–9360.
Juo P, Juo CJ, Yuan J and Blenis J. . 1998 Curr. Biol. 8: 1001–1008.
Kawahara A, Kobayashi T and Nagata S. . 1998 Oncogene 17: 2549–2554.
Kataoka T, Schroter M, Hahne M, Schneider P, Irmler M, Thome M, Froelich CJ and Tschopp J. . 1998 Immunol. 161: 3936–3942.
Kluck RM, Bossy Wetzel E, Green DR and Newmeyer DD. . 1997 Science 275: 1132–1136.
Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MS, Rakic P and Flavell RA. . 1998 Cell 94: 325–337.
Li F, Srinivasan A, Wang Y, Armstrong RC and Tomaselli KJ. . 1997a J. Biol. Chem. 272: 30299–30305.
Li H, Zhu H, Xu C-J and Yuan J. . 1998 Cell 94: 491–501.
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES and Wang X. . 1997b Cell 91: 479–489.
Los M, Wesselborg S and Schulze-Osthoff K. . 1999 Immunity 10: 629–639.
Luo X, Budihardjo I, Zou H, Slaughter C and Wang X. . 1998 Cell 94: 481–490.
Martin DA, Siegel RM, Zheng L and Lenardo MJ. . 1998 J. Biol. Chem. 273: 4345–4349.
Moriishi K, Huang DC, Cory S and Adams JM. . 1999 Proc. Natl. Acad. Sci. USA 96: 9683–9688.
Müller M, Strand S, Hug H, Heinemann E-M, Walczak H, Hofmann WJ, Stremmel W, Krammer PH and Galle PR. . 1997 J. Clin. Invest. 99: 403–413.
Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME and Dixit VM. . 1996 Cell 85: 817–827.
Muzio M, Stockwell BR, Stennicke HR, Salvesen GS and Dixit VM. . 1998 J. Biol. Chem. 273: 2926–2930.
Nicoletti I, Migliorati G, Pagliacci MC, Grignani F and Riccardi C. . 1991 J. Immunol. Methods 139: 271–279.
Qin H, Srinivasula SM, Wu G, Fernandes-Alnemri T, Alnemri ES and Shi Y. . 1999 Nature 399: 549–557.
Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin K-M, Krammer PH and Peter ME. . 1998 EMBO J. 17: 1675–1687.
Schulze-Osthoff K, Ferrari D, Los M, Wesselborg S and Peter ME. . 1998 Eur. J. Biochem. 254: 439–459.
Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD, Wang HG, Reed JC, Nicholson DW, Alnemri ES, Green DR and Martin SJ. . 1999 J. Cell. Biol. 144: 281–292.
Slee EA, Keogh SA and SJ Martin SJ. . 2000 Cell Death Differ. 7: 556–565.
Srinivasula SM, Ahmad M, Fernandes Alnemri T, Litwack G and Alnemri ES. . 1996 Proc. Natl. Acad. Sci. USA 93: 14486–14491.
Srinivasula SM, Ahmad M, Ottilie S, Bullrich F, Banks S, Wang Y, Fernandes Alnemri T, Croce CM, Litwack G, Tomaselli KJ, Armstrong RC and Alnemri ES. . 1997 J. Biol. Chem. 272: 18542–18545.
Srinivasula SM, Ahmad M, Fernandes-Alnemri T and Alnemri ES. . 1998 Mol. Cell 1: 949–957.
Stroh C and Schulze-Osthoff K. . 1998 Cell Death Differ. 5: 997–1000.
Sun XM, MacFarlane M, Zhuang J, Wolf BB, Green DR and Cohen GM. . 1999 J. Biol. Chem. 274: 5053–5060.
Tang D, Lahti JM and Kidd VJ. . (2000) J. Biol. Chem. 275: 9303–9307.
Thornberry NA and Lazebnik Y. . 1998 Science 281: 1312–1316.
Tolomeo M, Dusonchet L, Meli M, Grimaudo S, D'Alessandro N, Papoff G, Ruberti G and Rausa L. . 1998 Cell Death Differ. 5: 735–742.
Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, Rebrikov D, Brodianski VM, Kemper OC, Kollet O, Lapidot T, Soffer D, Sobe T, Avraham KB, Goncharov T, Holtmann H, Lonai P and Wallach D. . 1998 Immunity 9: 267–276.
Villunger A, Egle A, Kos M, Hartmann BL, Geley S, Kofler R and Greil R. . 1997 Cancer Res. 57: 3331–3334.
Wajant H, Johannes FJ, Haas E, Siemienski K, Schwenzer R, Schubert G, Weiss T, Grell M and Scheurich P. . 1998 Curr. Biol. 8: 113–116.
Wesselborg S, Engels IH, Rossmann E, Los M and Schulze-Osthoff K. . 1999 Blood 93: 3053–3063.
Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP and Wang X. . 1997 Science 275: 1129–1132.
Acknowledgements
The authors wish to thank Drs ES Alnemri, J Blenis, Y Lazebnik, CB Thompson, J Tschopp, J Yuan, P Vandenabeele and H Walczak for providing many valuable cell lines and reagents. This work was supported in part by grants from the Federal Ministry of Education, Science, Research and Technology (Fö. 01KS9602) and the Interdisciplinary Center of Clinical Research Center (IZKF) Tübingen. S Wesselborg acknowledges a fellowship from the Federal Ministry of Education, Science, Research and Technology, and C Berg from the Fortune Program of the University of Tübingen.
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Engels, I., Stepczynska, A., Stroh, C. et al. Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis. Oncogene 19, 4563–4573 (2000). https://doi.org/10.1038/sj.onc.1203824
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DOI: https://doi.org/10.1038/sj.onc.1203824
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