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Gene expression profiling of human colon cancer cells following inhibition of signal transduction by 17-allylamino-17-demethoxygeldanamycin, an inhibitor of the hsp90 molecular chaperone

Oncogene volume 19, pages 4125–4133 (2000)Cite this article

Abstract

A number of molecular therapeutic agents, derived from exploiting our knowledge of the oncogenic pathways that are frequently deregulated in cancer, are now entering clinical trials. One of these is the novel agent 17-allylamino-17-demethoxygeldanamycin that acts to inhibit the hsp90 molecular chaperone. Treatment of four human colon cancer cell lines with iso-effective concentrations of this agent resulted in depletion of c-raf-1 and akt and inhibition of signal transduction. We have used gene expression array analysis to identify genes responsive to treatment with this drug. The expression of hsp90 client protein genes was not affected, but hsc hsp70, hsp90β, keratin 8, keratin 18 and caveolin-1 were deregulated following treatment. These observations were consistent with inhibition of signal transduction and suggested a possible mechanism of resistance or recovery from 17-allylamino-17-demethoxygeldanamycin treatment. The results shed light on the molecular mode of action of the hsp90 inhibitors, and suggest possible molecular markers of drug action for use in hypothesis testing clinical trials.

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Abbreviations

17-AAG:

17-allylamino-17-demethoxygeldanamycin

17-AG:

17-amino-17-demethoxygeldanmycin

hsp:

heat shock protein

hsc:

heat shock cognate

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Acknowledgements

Cancer Research Campaign funding is gratefully acknowledged by P Clarke, M Walton, I Judson and P Workman (grant number SP2330 and P Workman is a Cancer Research Campaign Life Fellow). A Maloney is supported by an Institute of Cancer Research studentship and I Hostein by Ligue Nationale Contre Le Cancer and the Haddow fund of the Institute of Cancer Research. We thank our colleagues in the Signal Transduction and Molecular Pharmacology Team for helpful discussion.

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  1. Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, E Block, 15, Cotswold Road, Sutton, SM2 5NG, Surrey, UK

    Paul A Clarke, Isabelle Hostein, Udai Banerji, Francesca Di Stefano, Alison Maloney, Mike Walton, Ian Judson & Paul Workman

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Clarke, P., Hostein, I., Banerji, U. et al. Gene expression profiling of human colon cancer cells following inhibition of signal transduction by 17-allylamino-17-demethoxygeldanamycin, an inhibitor of the hsp90 molecular chaperone. Oncogene 19, 4125–4133 (2000). https://doi.org/10.1038/sj.onc.1203753

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