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Molecular ordering of hypoxia-induced apoptosis: critical involvement of the mitochondrial death pathway in a FADD/caspase-8 independent manner

Oncogene volume 23, pages 3757–3769 (2004)Cite this article

Abstract

Dys-regulated growth and improper angiogenesis commonly lead to areas of hypoxia in human tumors. Hypoxia is known to be associated with a worse outcome since a lack of oxygen interferes with the efficacy of chemotherapy or radiotherapy. In parallel, hypoxia-induced apoptosis may also impose a selection pressure favoring growth of more resistant tumor cells. However, the mechanisms of hypoxia-induced apoptosis and the relative contribution of intrinsic and extrinsic apoptotic pathways are not understood. Therefore, Jurkat cell lines with defined defects in the extrinsic or intrinsic signaling cascades were used to evaluate the role of either pathway for induction of apoptosis under hypoxic conditions. Jurkat cells were incubated in hypoxia and the rate of apoptosis induction was determined by Western blotting, fluorescence microscopy and flow cytometry. Hypoxia-induced apoptosis was not affected by lack of caspase-8 or FADD, whereas overexpression of Bcl-2 or expression of dominant-negative caspase-9 mutant rendered the cells resistant to hypoxia-induced apoptosis. These results suggest that hypoxia-induced apoptosis mainly relies on intrinsic, mitochondrial pathways, whereas extrinsic pathways have no significant implications in this process. Thus, in human tumors, hypoxia will mainly lead to the selection of hypoxia-resistant cells with defects in mitochondrial apoptosis signaling pathways.

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References

  • Alarcon RM, Denko NC and Giaccia AJ . (2001). Novartis Found. Symp., 240, 115–128 discussion 128–132.

  • Banasiak KJ, Cronin T and Haddad GG . (1999). Brain Res. Mol. Brain Res., 72, 214–225.

  • Banasiak KJ and Haddad GG . (1998). Brain Res., 797, 295–304.

  • Belka C, Betsch A, Marini P, Jendrossek V, Bamberg M and Budach W . (2003a). Strahlenther. Onkol., 179, 141–151.

  • Belka C and Budach W . (2002). Int. J. Radiat. Biol., 78, 643–658.

  • Belka C, Gruber C, Jendrossek V, Wesselborg S and Budach W . (2003b). Oncogene, 22, 176–185.

  • Belka C, Heinrich V, Marini P, Faltin H, Schulze-Osthoff K, Bamberg M and Budach W . (1999a). Int. J. Radiat. Biol., 75, 1257–1264.

  • Belka C, Marini P, Budach W, Schulze-Osthoff K, Lang F, Gulbins E and Bamberg M . (1998). Radiat. Res., 149, 588–595.

  • Belka C, Marini P, Lepple-Wienhues A, Budach W, Jekle A, Los M, Lang F, Schulze-Osthoff K, Gulbins E and Bamberg M . (1999b). Oncogene, 18, 4983–4992.

  • Belka C, Rudner J, Wesselborg S, Stepczynska A, Marini P, Lepple-Wienhues A, Faltin H, Bamberg M, Budach W and Schulze-Osthoff K . (2000). Oncogene, 19, 1181–1190.

  • Bialik S, Geenen DL, Sasson IE, Cheng R, Horner JW, Evans SM, Lord EM, Koch CJ and Kitsis RN . (1997). J. Clin. Invest., 100, 1363–1372.

  • Blagosklonny MV, An WG, Romanova LY, Trepel J, Fojo T and Neckers L . (1998). J. Biol. Chem., 273, 11995–11998.

  • Chao W, Shen Y, Li L and Rosenzweig A . (2002). J. Biol. Chem., 277, 31639–31645.

  • Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T and Korsmeyer SJ . (2001). Mol. Cell, 8, 705–711.

  • Chinnaiyan AM, O’Rourke K, Tewari M and Dixit VM . (1995). Cell, 81, 505–512.

  • Engels IH, Stepczynska A, Stroh C, Lauber K, Berg C, Schwenzer R, Wajant H, Janicke RU, Porter AG, Belka C, Gregor M, Schulze-Osthoff K and Wesselborg S . (2000). Oncogene, 19, 4563–4573.

  • Felderhoff-Mueser U, Taylor DL, Greenwood K, Kozma M, Stibenz D, Joashi UC, Edwards AD and Mehmet H . (2000). Brain Pathol., 10, 17–29.

  • Ferrari D, Stepczynska A, Los M, Wesselborg S and Schulze-Osthoff K . (1998). J. Exp. Med., 188, 979–984.

  • Fischer U, Janicke RU and Schulze-Osthoff K . (2003). Cell Death Differ., 10, 76–100.

  • Gibson ME, Han BH, Choi J, Knudson CM, Korsmeyer SJ, Parsadanian M and Holtzman DM . (2001). Mol. Med., 7, 644–655.

  • Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW and Giaccia AJ . (1996). Nature, 379, 88–91.

  • Harris AL . (2002). Nat. Rev. Cancer, 2, 38–47.

  • Igney FH and Krammer PH . (2002). Nat. Rev. Cancer, 2, 277–288.

  • Jendrossek V, Handrick R and Belka C . (2003a). FASEB. J., 17, 1547–1549.

  • Jendrossek V, Muller I, Eibl H and Belka C . (2003b). Oncogene, 22, 2621–2631.

  • Khurana P, Ashraf QM, Mishra OP and Delivoria-Papadopoulos M . (2002). Neurochem. Res., 27, 931–938.

  • Kim CY, Tsai MH, Osmanian C, Graeber TG, Lee JE, Giffard RG, DiPaolo JA, Peehl DM and Giaccia AJ . (1997). Cancer Res., 57, 4200–4204.

  • Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ and Ashkenazi A . (2000). Immunity, 12, 611–620.

  • Kischkel FC, Lawrence DA, Tinel A, LeBlanc H, Virmani A, Schow P, Gazdar A, Blenis J, Arnott D and Ashkenazi A . (2001). J. Biol. Chem., 2, 2.

  • Kluck RM, Bossy-Wetzel E, Green DR and Newmeyer DD . (1997). Science, 275, 1132–1136.

  • Kowaltowski AJ, Cosso RG, Campos CB and Fiskum G . (2002). J. Biol. Chem., 277, 42802–42807.

  • Li H, Zhu H, Xu CJ and Yuan J . (1998). Cell, 94, 491–501.

  • Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES and Wang X . (1997). Cell, 91, 479–489.

  • Lopez-Hernandez FJ, Ortiz MA, Bayon Y and Piedrafita FJ . (2003). Cell Death Differ., 24, 24.

  • Malhotra R, Lin Z, Vincenz C and Brosius III FC . (2001). Am. J. Physiol. Cell Physiol., 281, C1596–C1603.

  • Medema JP, Scaffidi C, Kischkel FC, Shevchenko A, Mann M, Krammer PH and Peter ME . (1997). EMBO J., 16, 2794–2804.

  • Mogi M, Fukuo K, Yang J, Suhara T and Ogihara T . (2001). Lab. Invest., 81, 177–184.

  • 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.

  • Newton K and Strasser A . (2000). J. Exp. Med., 191, 195–200.

  • Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T and Tanaka N . (2000). Science, 288, 1053–1058.

  • Park WY, Hwang CI, Im CN, Kang MJ, Woo JH, Kim JH, Kim YS, Kim H, Kim KA, Yu HJ, Lee SJ, Lee YS and Seo JS . (2002). Oncogene, 21, 8521–8528.

  • Qin JZ, Chaturvedi V, Denning MF, Bacon P, Panella J, Choubey D and Nickoloff BJ . (2002). Oncogene, 21, 2991–3002.

  • Renz A, Berdel WE, Kreuter M, Belka C, Schulze-Osthoff K and Los M . (2001). Blood, 98, 1542–1548.

  • Rudner J, Belka C, Marini P, Wagner RJ, Faltin H, Lepple-Wienhues A, Bamberg M and Budach W . (2001a). Int. J. Radiat. Biol., 77, 1–11.

  • Rudner J, Jendrossek V and Belka C . (2002). Apoptosis, 7, 441–447.

  • Rudner J, Lepple-Wienhues A, Budach W, Berschauer J, Friedrich B, Wesselborg S, Schulze-Osthoff K and Belka C . (2001b). J. Cell. Sci., 114, 4161–4172.

  • 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.

  • Shimizu S, Eguchi Y, Kamiike W, Itoh Y, Hasegawa J, Yamabe K, Otsuki Y, Matsuda H and Tsujimoto Y . (1996). Cancer Res., 56, 2161–2166.

  • Shimizu S, Eguchi Y, Kosaka H, Kamiike W, Matsuda H and Tsujimoto Y . (1995). Nature, 374, 811–813.

  • Soengas MS, Alarcon RM, Yoshida H, Giaccia AJ, Hakem R, Mak TW and Lowe SW . (1999). Science, 284, 156–159.

  • Steinbach JP, Wolburg H, Klumpp A, Probst H and Weller M . (2003). Cell Death Differ., 10, 823–832.

  • Stepczynska A, Lauber K, Engels IH, Janssen O, Kabelitz D, Wesselborg S and Schulze-Osthoff K . (2001). Oncogene, 20, 1193–1202.

  • Suzuki H, Tomida A and Tsuruo T . (2001). Oncogene, 20, 5779–5788.

  • Tamatani M, Ogawa S and Tohyama M . (1998). Brain. Res. Mol. Brain Res., 58, 27–39.

  • Tsujimoto Y, Shimizu S, Eguchi Y, Kamiike W and Matsuda H . (1997). Leukemia, 11, 380–382.

  • Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ and Vaux DL . (2000). Cell, 102, 43–53.

  • von Haefen C, Wieder T, Gillissen B, Starck L, Graupner V, Dorken B and Daniel PT . (2002). Oncogene, 21, 4009–4019.

  • 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.

  • Weinmann M, Marini P, Jendrossek V, Betsch A, Goecke B, Budach W and Belka C . (2004). Int. J. Radiat. Oncol. Biol. Phys., 58, 386–396.

  • Wieder T, Essmann F, Prokop A, Schmelz K, Schulze-Osthoff K, Beyaert R, Dorken B and Daniel PT . (2001). Blood, 97, 1378–1387.

  • Yaniv G, Shilkrut M, Lotan R, Berke G, Larisch S and Binah O . (2002). Cardiovasc. Res., 54, 611–623.

  • Yoshimura S, Banno Y, Nakashima S, Takenaka K, Sakai H, Nishimura Y, Sakai N, Shimizu S, Eguchi Y, Tsujimoto Y and Nozawa Y . (1998). J. Biol. Chem., 273, 6921–6927.

  • Zhu H, McElwee-Witmer S, Perrone M, Clark KL and Zilberstein A . (2000). Cell Death Differ., 7, 773–784.

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Acknowledgements

The experiments presented here were supported by a ‘Fortune-grant’ (Project Nr. F 1352253) of the University of Tübingen to MW and a grant to CB and VJ by Deutsche Krebshilfe/Mildred Scheel Stiftung (10-1970-Be3). We are thankful to P. Juo and J. Blenis (Boston, MA, USA) for the caspase-8- and FADD-negative Jurkat cells and to E Alnemri (Philiadelphia, USA) for the caspase-9 DN construct.

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  1. Martin Weinmann and Verena Jendrossek: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Radiation Oncology, University of Tübingen, Germany

    Martin Weinmann, Verena Jendrossek, Rene Handrick, Barbara Goecke & Claus Belka

  2. Department of Radiation Oncology, Charite Berlin, Germany

    Dilek Güner

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  1. Martin Weinmann
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Correspondence to Claus Belka.

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Weinmann, M., Jendrossek, V., Handrick, R. et al. Molecular ordering of hypoxia-induced apoptosis: critical involvement of the mitochondrial death pathway in a FADD/caspase-8 independent manner. Oncogene 23, 3757–3769 (2004). https://doi.org/10.1038/sj.onc.1207481

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