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  • Original Paper
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Roscovitine sensitizes glioma cells to TRAIL-mediated apoptosis by downregulation of survivin and XIAP

Oncogene volume 23, pages 446–456 (2004)Cite this article

Abstract

The cytotoxic effect of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is limited in many glioma cell lines. However, treatment with TRAIL in combination with subtoxic doses of roscovitine, a specific inhibitor of Cdc2 and Cdk2, induced rapid apoptosis in TRAIL-resistant glioma cells. Roscovitine could sensitize Bcl-2- or Bcl-xL-overexpressing glioma cells, but not human astrocytes, to TRAIL-induced apoptosis, offering an attractive strategy for safely treating resistant gliomas. Treatment with roscovitine significantly inhibited Cdc2 activity, and expression of a dominant-negative Cdc2 mutant sensitized glioma cells to TRAIL-induced apoptosis. While the proteolytic processing of procaspase-3 by TRAIL was partially blocked in U87MG and T98 glioma cells, treatment with roscovitine recovered TRAIL-induced activation of caspases very efficiently in these cells. We found that treatment with roscovitine or expression of a dominant-negative Cdc2 mutant downregulated the protein levels of survivin and XIAP, two major caspase inhibitors. Overexpression of survivin or XIAP attenuated the apoptosis induced by roscovitine and TRAIL. Taken together, these results suggest that downregulation of survivin and XIAP by subtoxic doses of roscovitine contributes to the amplification of caspase cascades, thereby overcoming glioma cell resistance to TRAIL-mediated apoptosis.

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Abbreviations

TRAIL:

TNF-related apoptosis-inducing ligand

GFAP:

glial fibrillary acidic protein

PBS:

phosphate-buffered saline

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

PAGE:

polyacrylamide gel electrophoresis

SDS–PAGE:

sodium dodecyl sulfate–polyacrylamide gel electrophoresis

DN:

dominant negative

FLIP:

FLICE-inhibitory protein

IAP:

inhibitor of apoptosis

XIAP:

X-chromosome-linked IAP

FITC:

fluorescein isothiothyanate

RT–PCR:

reverse transcriptase–polymerase chain reaction

References

  • Adams JM and Corry S . (1998). Science, 281, 1322–1326.

  • Altieri DC . (2003). Nat. Rev. Cancer, 3, 46–54.

  • Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, DeForge L, Koumenis IL, Lewis D, Harris L, Bussiere J, Koeppen H, Shahrokh Z and Schwall RH . (1999). J. Clin. Invest., 104, 155–162.

  • Asselin E, Mills GB and Tsang BK . (2001). Cancer Res., 61, 1862–1868.

  • Badie C, Itzhaki JE, Sullivan MJ, Carpenter AJ and Porter AC . (2000). Mol. Cell. Biol., 20, 2538–2366.

  • Chakravarti A, Noll E, Black PM, Finkelstein DF, Finkelstein DM, Dyson NJ and Loeffler JS . (2002). J. Clin. Oncol., 20, 1063–1068.

  • De Azevedo WF, Leclerc S, Meijer L, Havlicek L, Strnad M and Kim SH . (1997). Eur. J. Biochem., 243, 518–526.

  • Deveraux QL, Leo E, Stennicke HR, Welsh K, Salvesen GS and Reed JC . (1999b). EMBO J., 18, 5241–5251.

  • Deveraux QL and Reed JC . (1999a). Genes Dev., 13, 239–252.

  • Earnshaw WC, Martins LM and Kaufmann SH . (1999). Annu. Rev. Biochem., 68, 383–424.

  • Gazzaniga P, Gradilone A, Giuliani L, Gandini O, Silvestri I, Nofroni I, Saccani G, Frati L and Agliano AM . (2003). Ann. Oncol., 14, 85–90.

  • Gibson SB, Oyer R, Spalding AC, Anderson SM and Johnson GL : Mol. Cell. Biol. (2000) 20, 205–212.

  • Grant S and Roberts JD . (2003). Drug Resist. Updat., 6, 15–26.

  • Griffith TS, Fialkov JM, Scott DL, Azuhata T, Williams RD, Wall NR, Altieri DC and Sandler AD . (2002). Cancer Res., 62, 3093–3099.

  • Hao C, Beguinot F, Condorelli G, Trencia A, Van Meir EG, Yong VW, Parney IF, Roa WH and Petruk KC . (2001). Cancer Res., 61, 1162–1170.

  • Huang DC, Cory S and Strasser A . (1997). Oncogene, 14, 405–414.

  • Kim SU . (1985). J. Neuroimmunol., 8, 255–282.

  • Kim SU, Moretto G, Lee V and Yu RK . (1986). J. Neurosci. Res., 15, 303–321.

  • Knight MJ, Riffkin CD, Muscat AM, Ashley DM and Hawkins CJ . (2001). Oncogene, 20, 5789–5798.

  • Kobayashi K, Hatano M, Otaki M, Ogasawara T and Tokuhisa T . (1999). Proc. Natl. Acad. Sci. USA, 96, 1457–1462.

  • Kroemer G and Reed JC . (2000). Nat. Med., 6, 513–519.

  • Legler JM, Ries LA, Smith MA, Warren JL, Heineman EF, Kaplan RS and Linnet MS . (1999). J. Natl. Cancer Inst., 91, 1382–1390.

  • Nagane M, Pan G, Weddle JJ, Dixit VM, Cavenee WK and Huang HJ . (2000). Cancer Res., 60, 847–853.

  • Ng CP, Zisman A and Bonavida B . (2002). Prostate, 53, 286–299.

  • Nomura T, Mimata H, Takeuchi Y, Yamamoto H, Miyamoto E and Nomura Y . (2003). Urol. Res., 31, 37–44.

  • O'Connor DS, Wall NR, Proter AC and Altieri DC . (2002). Cancer Cell, 2, 43–54.

  • Rieger J, Naumann U, Glaser T, Ashkenazi A and Weller M . (1998). FEBS Lett., 427, 124–128.

  • Rokudai S, Fujita N, Hashimoto Y and Tsuruo T . (2000). J. Cell Physiol., 182, 290–296.

  • Roth W, Isenmann S, Naumann U, Kugler S, Bahr M, Dichgans J, Ashkenazi A and Weller M . (1999). Biochem. Biophys. Res. Commun., 265, 479–483.

  • Schwartz GK, Ilson D, Saltz L, O'Reilly E, Tong W, Maslak P, Werner J, Perkins P, Stoltz M and Kelson D . (2001). J. Clin. Oncol., 19, 1985–1992.

  • Sehgal A . (1998). Semin. Surg. Oncol., 14, 3–12.

  • Shapiro GI, Supko JG, Patterson A, Lynch C, Lucca J, Zacarola PF, Muzikansky A, Wright JJ, Lynch Jr TJ and Rollins BJ . (2001). Clin. Cancer Res., 7, 1590–1599.

  • Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P and Ashkenazi A . (1997). Science, 277, 818–821.

  • Suzuki Y, Nakabayashi Y and Takahashi R . (2001). Proc. Natl. Acad. Sci. USA, 98, 8662–8667.

  • Tewari M, Beidler DR and Dixit VM . (1995). J. Biol. Chem., 270, 18738–18741.

  • Thakkar H, Chen X, Tyan F, Gim S, Robinson H, Lee C, Pandey SK, Nwokorie C, Onwudiwe N and Srivastava RK . (2001). J. Biol. Chem., 276, 38361–38369.

  • Tschopp J, Irmler M and Thome M . (1998). Curr. Opin. Immunol., 10, 118–126.

  • Van den Heuvel S and Harlow E . (1993). Science, 262, 2050–2054.

  • Wagenknecht B, Glaser T, Naumann U, Kugler S, Isenmann S, Bahr M, Korneluk R, Liston P and Weller M . (1999). Cell. Death Differ., 6, 370–376.

  • Weber RG, Rieger J, Naumann U, Lichter P and Weller M . (2001). Int. J. Cancer, 91, 213–218.

  • Zaffaroni N and Daidone MG . (2002). Drug Resist. Updat., 5, 65–72.

  • Zhang XD, Zhang XY, Gray CP, Nguyen T and Hersey P . (2001). Cancer Res., 61, 7339–7348.

  • Zhao J, Tenev T, Martins LM, Downward J and Lemoine NR . (2000). J. Cell Sci., 113, 4363–4371.

  • Zhou Q, Snipas S, Orth K, Muzio M, Dixit VM and Salvesen GS . (1997). J. Biol. Chem., 272, 7797–8000.

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Acknowledgements

We thank Professor E Harlow (Massachusetts General Hospital Cancer Center) for generously providing the plasmids expressing HA-tagged dominant-negative Cdc2 and Cdk2 mutants. We also thank Professor A Strasser (The Walter and Eliza Hall Institute of medical Research) for providing us with the Bcl-2, Bcl-xL, and 19-kDa expression vector; and Professor VM Dixit (University of Michigan Medical School) for providing us with the CrmA expression vector. We thank Professor T Tokuhisa (Chiba University) for providing a flag/survivin fusion protein expression vector, and Professor Y Nomura (Oita Medical University) for providing the XIAP expression vector. This study was supported by a grant from the KOSEF/BDRC Ajou University (R11-1998-052-08005).

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Authors and Affiliations

  1. Institute for Medical Sciences, Ajou University School of Medicine, Suwon, 442-749, South Korea

    Eun Hee Kim & Kyeong Sook Choi

  2. Brain Disease Research Center, Ajou University School of Medicine, Suwon, 442-749, South Korea

    Seung U Kim & Kyeong Sook Choi

  3. Department of Microbiology, Dankook University College of Medicine, Cheonan, 330-714, South Korea

    Deug Y Shin

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Correspondence to Kyeong Sook Choi.

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Kim, E., Kim, S., Shin, D. et al. Roscovitine sensitizes glioma cells to TRAIL-mediated apoptosis by downregulation of survivin and XIAP. Oncogene 23, 446–456 (2004). https://doi.org/10.1038/sj.onc.1207025

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