Abstract
During the process of death receptor-mediated apoptosis, Bid is cleaved by activated caspase-8, and then cleaved Bid conveys apoptotic signals to the mitochondria by activating Bax/Bak. In the present study, we found that D609 (an antitumor drug with multiple activities) blocks Fas-induced apoptosis. D609 did not interfere with activation of caspase-8 and cleavage of Bid, whereas it blocked cytochrome c release from the mitochondria by inhibiting the activation of Bax and Bak. D609 had no protective effect against apoptosis of SKW6.4 cells, which are typical type I cells. Studies using permeabilized cells revealed that in addition to activation of caspase-8, Fas activated a distinct and D609-sensitive signaling pathway that transmitted signal(s) sensitizing the mitochondria to apoptotic stimuli, and that D609 itself promoted mitochondrial resistance to apoptotic stimuli.
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References
Amtmann E . (1996). Drugs Exp. Clin. Res., 22, 287–294.
Amtmann E and Sauer G . (1987). Cancer Lett., 35, 237–244.
Antonsson B, Montessuit S, Lauper S, Eskes R and Martinou JC . (2000). Biochem. J., 345 (Part 2), 271–278.
Antonsson B, Montessuit S, Sanchez B and Martinou JC . (2001). J. Biol. Chem., 276, 11615–11623.
Boesen-de Cock JG, Tepper AD, de Vries E, van Blitterswijk WJ and Borst J . (1999). J. Biol. Chem., 274, 14255–14261.
Boldin MP, Goncharov TM, Goltsev YV and Wallach D . (1996). Cell, 85, 803–815.
Cheng EH, Sheiko TV, Fisher JK, Craigen WJ and Korsmeyer SJ . (2003). Science, 301, 513–517.
Cifone MG, Roncaioli P, De Maria R, Camarda G, Santoni A, Ruberti G and Testi R . (1995). EMBO J., 14, 5859–5868.
Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S, Maundrell K, Antonsson B and Martinou JC . (1999). J. Cell Biol., 144, 891–901.
Desbarats J, Birge RB, Mimouni-Rongy M, Weinstein DE, Palerme JS and Newell MK . (2003). Nat. Cell Biol., 5, 118–125.
Eischen CM, Dick CJ and Leibson PJ . (1994). J. Immunol., 153, 1947–1954.
Epand RF, Martinou JC, Fornallaz-Mulhauser M, Hughes DW and Epand RM . (2002). J. Biol. Chem., 277, 32632–32639.
Eskes R, Desagher S, Antonsson B and Martinou JC . (2000). Mol. Cell. Biol., 20, 929–935.
Griffiths GJ, Dubrez L, Morgan CP, Jones NA, Whitehouse J, Corfe BM, Dive C and Hickman JA . (1999). J. Cell Biol., 144, 903–914.
Gross A, Jockel J, Wei MC and Korsmeyer SJ . (1998). EMBO J., 17, 3878–3885.
Hsu YT and Youle RJ . (1998). J. Biol. Chem., 273, 10777–10783.
Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH and Peter ME . (1995). EMBO J., 14, 5579–5588.
Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R, Green DR and Newmeyer DD . (2002). Cell, 111, 331–342.
Lambert C, Landau AM and Desbarats J . (2003). Apoptosis, 8, 551–562.
Li H, Zhu H, Xu CJ and Yuan J . (1998a). Cell, 94, 491–501.
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES and Wang X . (1997). Cell, 91, 479–489.
Li Y, Maher P and Schubert D . (1998b). Proc. Natl. Acad. Sci. USA, 95, 7748–7753.
Lin T, Genestier L, Pinkoski MJ, Castro A, Nicholas S, Mogil R, Paris F, Fuks Z, Schuchman EH, Kolesnick RN and Green DR . (2000). J. Biol. Chem., 275, 8657–8663.
Liu X, Kim CN, Yang J, Jemmerson R and Wang X . (1996). Cell, 86, 147–157.
Luo X, Budihardjo I, Zou H, Slaughter C and Wang X . (1998). Cell, 94, 481–490.
Machleidt T, Kramer B, Adam D, Neumann B, Schutze S, Wiegmann K and Kronke M . (1996). J. Exp. Med., 184, 725–733.
Matsko CM, Hunter OC, Rabinowich H, Lotze MT and Amoscato AA . (2001). Biochem. Biophys. Res. Commun., 287, 1112–1120.
Nomura M, Shimizu S, Ito T, Narita M, Matsuda H and Tsujimoto Y . (1999). Cancer Res., 59, 5542–5548.
Paris F, Grassme H, Cremesti A, Zager J, Fong Y, Haimovitz-Friedman A, Fuks Z, Gulbins E and Kolesnick R . (2001). J. Biol. Chem., 276, 8297–8305.
Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH and Peter ME . (1998). EMBO J., 17, 1675–1687.
Schutze S, Potthoff K, Machleidt T, Berkovic D, Wiegmann K and Kronke M . (1992). Cell, 71, 765–776.
Shimizu S and Tsujimoto Y . (2000). Proc. Natl. Acad. Sci. USA, 97, 577–582.
Shinohara H, Yagita H, Ikawa Y and Oyaizu N . (2000). Cancer Res., 60, 1766–1772.
Wallach D, Varfolomeev EE, Malinin NL, Goltsev YV, Kovalenko AV and Boldin MP . (1999). Annu. Rev. Immunol., 17, 331–367.
Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB and Korsmeyer SJ . (2000). Genes Dev., 14, 2060–2071.
Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB and Korsmeyer SJ . (2001). Science, 292, 727–730.
Wiegmann K, Schutze S, Machleidt T, Witte D and Kronke M . (1994). Cell, 78, 1005–1015.
Wolter KG, Hsu YT, Smith CL, Nechushtan A, Xi XG and Youle RJ . (1997). J. Cell Biol., 139, 1281–1292.
Yang X, Khosravi-Far R, Chang HY and Baltimore D . (1997). Cell, 89, 1067–1076.
Yethon JA, Epand RF, Leber B, Epand RM and Andrews DW . (2003). J. Biol. Chem., 278, 48935–48941.
Yin XM, Wang K, Gross A, Zhao Y, Zinkel S, Klocke B, Roth KA and Korsmeyer SJ . (1999). Nature, 400, 886–891.
Zhang L, Shimizu S, Sakamaki K, Yonehara S and Tsujimoto Y . (2004). J. Biol. Chem., 279, 33865–33874.
Zhou D, Lauderback CM, Yu T, Brown SA, Butterfield DA and Thompson JS . (2001). J. Pharmacol. Exp. Ther., 298, 103–109.
Acknowledgements
We thank Drs K Sakamaki and S Yonehara for kindly providing caspase-8-deficient MEFs. This study was supported in part by a grant for Scientific Research on Priority Areas, a grant for Center of Excellence Research, a grant for the 21st century COE program, and a grant for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan.
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Zhang, L., Shimizu, S. & Tsujimoto, Y. Two distinct Fas-activated signaling pathways revealed by an antitumor drug D609. Oncogene 24, 2954–2962 (2005). https://doi.org/10.1038/sj.onc.1208388
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DOI: https://doi.org/10.1038/sj.onc.1208388