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Array-based comparative gene expression analysis of tumor cells with increased apoptosis resistance after hypoxic selection

Oncogene volume 24, pages 5914–5922 (2005)Cite this article

Abstract

Tumor hypoxia is an adverse prognostic factor. In a recent study, we could demonstrate that cyclic hypoxia selects for hypoxia-tolerant tumor cells, which are cross-resistant to other stimuli of mitochondrial death pathways. In contrast, sensitivity of the cells to death-receptor ligands was mainly not affected. The aim of the present study was to further elucidate cellular changes induced by cyclic hypoxia and to identify alterations in gene expression pattern upon hypoxic selection by means of DNA-microarray analysis. Our data reveal that cyclic hypoxia resulted in the selection of cells with resistance to doxorubicine and radiation. Furthermore, hypoxic selection was accompanied by constitutive changes of the gene expression pattern with downregulation of 156 and upregulation of 82 genes. Most of the differentially regulated genes were involved in cellular responses to hypoxia and reoxygenation. While many of the genes that were downregulated upon hypoxic selection represent genes that are usually upregulated by acute hypoxia, the genes that were upregulated represent genes that are involved in stress resistance and anti-apoptotic signalling. Most importantly, hypoxic selection was not associated with changes of single apoptosis relevant genes, but with alterations in gene expression levels of a wide variety of genes indicating a more complex adaptation process.

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References

  • Arlt A, Kruse ML, Breitenbroich M, Gehrz A, Koc B, Minkenberg J, Folsch UR and Schafer H . (2003). Oncogene, 22, 3343–3351.

  • Baltathakis I, Alcantara O and Boldt DH . (2001). J. Cell Biochem., 83, 281–290.

  • Beere HM, Wolf BB, Cain K, Mosser DD, Mahboubi A, Kuwana T, Tailor P, Morimoto RI, Cohen GM and Green DR . (2000). Nat. Cell Biol., 2, 469–475.

  • Bode JG, Gatsios P, Ludwig S, Rapp UR, Haussinger D, Heinrich PC and Graeve L . (1999). J. Biol. Chem., 274, 30222–30227.

  • Chandrasekar B, Colston JT, de la Rosa SD, Rao PP and Freeman GL . (2003). Biochem. Biophys. Res. Commun., 303, 1152–1158.

  • Collard CD, Vakeva A, Bukusoglu C, Zund G, Sperati CJ, Colgan SP and Stahl GL . (1997). Circulation, 96, 326–333.

  • Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC and Colgan SP . (2002). Cancer Res., 62, 3387–3394.

  • Di Ilio C, Angelucci S, Bucciarelli T, Pennelli A, Petruzzelli R, Di Giulio C, Miranda M, Amicarelli F and Sacchetta P . (1996). Biochim. Biophys. Acta, 1312, 125–131.

  • Dong Z and Wang J . (2004). J. Biol. Chem., 279, 9215–9221, [Epub 2003 Dec 15].

  • Fan C, Li Q, Ross D and Engelhardt JF . (2003). J. Biol. Chem., 278, 2072–2080.

  • Fujise K, Zhang D, Liu J and Yeh ET . (2000). J. Biol. Chem., 275, 39458–39465.

  • Garrido C, Schmitt E, Cande C, Vahsen N, Parcellier A and Kroemer G . (2003). Cell Cycle, 2, 579–584.

  • Gordon L, Wharton J, Moore SE, Flanigan TP, Gulbenkian S, Walsh FS, David-Ferreira JF, Winter RJ and Polak JM . (1990). Life Sci., 47, 601–609.

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

  • Gray LH, Conger AD, Ebert M, Hornsey S and Scott OC . (1953). Br. J. Radiol., 26, 638–648.

  • Gruber C, Henkel M, Budach W, Belka C and Jendrossek V . (2004). Biochem. Pharmacol., 67, 1859–1872.

  • Guo G, Yan-Sanders Y, Lyn-Cook BD, Wang T, Tamae D, Ogi J, Khaletskiy A, Li Z, Weydert C, Longmate JA, Huang TT, Spitz DR, Oberley LW and Li JJ . (2003). Mol. Cell Biol., 23, 2362–2378.

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

  • Hockel M, Schlenger K, Hockel S and Vaupel P . (1999). Cancer Res., 59, 4525–4528.

  • Ichinose F, Ullrich R, Sapirstein A, Jones RC, Bonventre JV, Serhan CN, Bloch KD and Zapol WM . (2002). J. Clin. Invest., 109, 1493–1500.

  • Jaattela M . (1999). Exp. Cell Res., 248, 30–43.

  • Kacimi R, Karliner JS, Koudssi F and Long CS . (1998). Circ. Res., 82, 576–586.

  • Kobayashi K, Inohara N, Hernandez LD, Galan JE, Nunez G, Janeway CA, Medzhitov R and Flavell RA . (2002). Nature, 416, 194–199.

  • Kojima T, Takagi A, Maeda M, Segawa T, Shimizu A, Yamamoto K, Matsushita T and Saito H . (2001). Thromb. Haemost., 85, 793–799.

  • Konduri SD, Yanamandra N, Dinh DH, Olivero WC, Gujrati M, Foster DC, Kisiel W and Rao JS . (2003). Int. J. Oncol., 22, 1277–1283.

  • Kuperstein F, Reiss N, Koudinova N and Yavin E . (2001). J. Neurochem., 76, 758–767.

  • Lenaz G, Bovina C, D'Aurelio M, Fato R, Formiggini G, Genova ML, Giuliano G, Pich MM, Paolucci U, Castelli GP and Ventura B . (2002). Ann. NY Acad. Sci., 959, 199–213.

  • Leonard MO, Cottell DC, Godson C, Brady HR and Taylor CT . (2003). J. Biol. Chem., 278, 40296–40304.

  • Liu G, Loraine AE, Shigeta R, Cline M, Cheng J, Valmeekam V, Sun S, Kulp D and Siani-Rose MA . (2003). Nucleic. Acids. Res., 31, 82–86.

  • Luders J, Demand J, Papp O and Hohfeld J . (2000). J. Biol. Chem., 275, 14817–14823.

  • Magnusson KP, Satalino R, Qian W, Klein G and Wiman KG . (1998). Oncogene, 17, 2333–2337.

  • Matsui H, Ihara Y, Fujio Y, Kunisada K, Akira S, Kishimoto T and Yamauchi-Takihara K . (1999). Cardiovasc. Res., 42, 104–112.

  • Mehler MF, Haas KZ, Kessler JA and Stanton PK . (1992). Proc. Natl. Acad. Sci. USA, 89, 2461–2465.

  • Mochizuki S, Murase T, Yamaoka H, Ishiki M, Tada N and Nagano M . (1987). Basic. Res. Cardiol., 82, 45–52.

  • Poss KD and Tonegawa S . (1997). Proc. Natl. Acad. Sci. USA, 94, 10925–10930.

  • Reisdorph R and Lindahl R . (1998). Biochem. Biophys. Res. Commun., 249, 709–712.

  • Rockwell S, Yuan J, Peretz S and Glazer PM . (2001). Novartis. Found. Symp., 240, 133–142; discussion 142–151.

  • Semenza GL . (2003). Nat. Rev. Cancer, 3, 721–732.

  • Seta K, Kim HW, Ferguson T, Kim R, Pathrose P, Yuan Y, Lu G, Spicer Z and Millhorn DE . (2002). Ann. NY Acad. Sci., 971, 379–388.

  • Synnestvedt K, Furuta GT, Comerford KM, Louis N, Karhausen J, Eltzschig HK, Hansen KR, Thompson LF and Colgan SP . (2002). J. Clin. Invest., 110, 993–1002.

  • Townsend PA, Cutress RI, Sharp A, Brimmell M and Packham G . (2003). Cancer Res., 63, 4150–4157.

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

  • Weinmann M, Jendrossek V, Guner D, Goecke B and Belka C . (2004b). FASEB J., 18, 1906–1908.

  • Weinmann M, Jendrossek V, Handrick R, Guner D, Goecke B and Belka C . (2004c). Oncogene, 23, 3757–3769.

  • Weinmann M, Welz S and Bamberg M . (2003). Curr. Med. Chem. Anti-Canc. Agents, 3, 364–374.

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Acknowledgements

We are thankful to Dr Michael Bonin from the Microarray Facility of the University of Tübingen for his excellent advice regarding the DNA microarray experiments. The study was 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).

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  1. Department of Radiation Oncology, University of Tuebingen, Hoppe Seyler Str. 3, Tuebingen, D-72076, Germany

    Martin Weinmann, Claus Belka, Barbara Goecke, Ilka Müller, Michael Bamberg & Verena Jendrossek

  2. Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Humboldt University, Berlin, Germany

    Dilek Güner

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Correspondence to Verena Jendrossek.

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Weinmann, M., Belka, C., Güner, D. et al. Array-based comparative gene expression analysis of tumor cells with increased apoptosis resistance after hypoxic selection. Oncogene 24, 5914–5922 (2005). https://doi.org/10.1038/sj.onc.1208748

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