Disruption of the EF-2 kinase/Hsp90 protein complex: A possible mechanism to inhibit glioblastoma by geldanamycin

Jun Yang, Jin Ming Yang, Marie Iannone, Weichung Joe Shih, Yong Lin, William N. Hait

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Glioblastoma multiforme is the most treatment-resistant brain tumor. Elongation factor-2 (EF-2) kinase (calmodulin kinase III) is a unique protein kinase that is overexpressed in glioma cell lines and in human surgical specimens. Several mitogens activate this kinase and inhibitors block mitogen activation and produce cell death. Geldanamycin (GA) is a benzoquinone ansamycin antibiotic that disrupts Hsp90-protein interactions. Because EF-2 kinase is chaperoned by Hsp90, we investigated the effects of GA on the viability of glioma cells, the expression of EF-2 kinase protein, and the interaction between Hsp90 and EF-2 kinase. GA was a potent inhibitor of the clonogenicity of four glioma cells lines with IC50s ranging from 1 to 3 nM. 17-allylamino-17-demethoxygeldanamycin (17-AAG), a less toxic and less potent derivative of GA, inhibited the clonogenicity of glioma cells with IC50 values of 13 nM in C6 cells and 35 nM in T98G cells. Treatment of cell lines for 24-48 h of GA or 17-AAG disrupted EF-2-kinase/Hsp90 interactions as measured by coimmunoprecipitation, resulting in a decreased amount of recoverable kinase in cell lysates. The ability of GA to inhibit the growth of glioma cells was abrogated by overexpressing EF-2 kinase. In addition, 17-AAG significantly inhibited the growth of a glioma xenograft in nude mice. These studies demonstrate for the first time the activity of GAs against human gliomas in vitro and in vivo and suggest that destruction of EF-2 kinase may be an important cytotoxic mechanism of this unique class of drug.

Original languageEnglish (US)
Pages (from-to)4010-4016
Number of pages7
JournalCancer Research
Volume61
Issue number10
StatePublished - May 15 2001

Fingerprint

Elongation Factor 2 Kinase
Glioblastoma
Glioma
tanespimycin
Proteins
Mitogens
Cell Line
Phosphotransferases
Rifabutin
Calcium-Calmodulin-Dependent Protein Kinases
Poisons
Growth
geldanamycin
Heterografts
Nude Mice
Brain Neoplasms
Protein Kinases
Inhibitory Concentration 50
Cell Survival
Cell Death

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Yang, J., Yang, J. M., Iannone, M., Shih, W. J., Lin, Y., & Hait, W. N. (2001). Disruption of the EF-2 kinase/Hsp90 protein complex: A possible mechanism to inhibit glioblastoma by geldanamycin. Cancer Research, 61(10), 4010-4016.
Yang, Jun ; Yang, Jin Ming ; Iannone, Marie ; Shih, Weichung Joe ; Lin, Yong ; Hait, William N. / Disruption of the EF-2 kinase/Hsp90 protein complex : A possible mechanism to inhibit glioblastoma by geldanamycin. In: Cancer Research. 2001 ; Vol. 61, No. 10. pp. 4010-4016.
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Yang, J, Yang, JM, Iannone, M, Shih, WJ, Lin, Y & Hait, WN 2001, 'Disruption of the EF-2 kinase/Hsp90 protein complex: A possible mechanism to inhibit glioblastoma by geldanamycin', Cancer Research, vol. 61, no. 10, pp. 4010-4016.

Disruption of the EF-2 kinase/Hsp90 protein complex : A possible mechanism to inhibit glioblastoma by geldanamycin. / Yang, Jun; Yang, Jin Ming; Iannone, Marie; Shih, Weichung Joe; Lin, Yong; Hait, William N.

In: Cancer Research, Vol. 61, No. 10, 15.05.2001, p. 4010-4016.

Research output: Contribution to journalArticle

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T1 - Disruption of the EF-2 kinase/Hsp90 protein complex

T2 - A possible mechanism to inhibit glioblastoma by geldanamycin

AU - Yang, Jun

AU - Yang, Jin Ming

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AU - Hait, William N.

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Yang J, Yang JM, Iannone M, Shih WJ, Lin Y, Hait WN. Disruption of the EF-2 kinase/Hsp90 protein complex: A possible mechanism to inhibit glioblastoma by geldanamycin. Cancer Research. 2001 May 15;61(10):4010-4016.