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

P A Clarke; I Hostein; U Banerji; F D Stefano; A Maloney; M Walton; I Judson; P Workman

doi:10.1038/sj.onc.1203753

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. 2000 Aug 24;19(36):4125-33. doi: 10.1038/sj.onc.1203753.

Authors

P A Clarke¹, I Hostein, U Banerji, F D Stefano, A Maloney, M Walton, I Judson, P Workman

Affiliation

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

PMID: 10962573
DOI: 10.1038/sj.onc.1203753

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, hsp90beta, 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. Oncogene (2000) 19, 4125 - 4133

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibiotics, Antineoplastic / pharmacology*
Benzoquinones
Blotting, Western
Colonic Neoplasms
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
HSP70 Heat-Shock Proteins / biosynthesis
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
HSP90 Heat-Shock Proteins / genetics
HSP90 Heat-Shock Proteins / metabolism
Humans
In Vitro Techniques
Lactams, Macrocyclic
Lymphocytes / drug effects
Oncogene Protein v-akt
Polymerase Chain Reaction
Protein Serine-Threonine Kinases / antagonists & inhibitors
Proto-Oncogene Proteins c-raf / metabolism
RNA, Messenger / analysis
RNA, Neoplasm / analysis
RNA, Neoplasm / metabolism
Retroviridae Proteins, Oncogenic / metabolism
Rifabutin / analogs & derivatives*
Rifabutin / pharmacology
Signal Transduction / drug effects*
Tumor Cells, Cultured

Substances

Antibiotics, Antineoplastic
Benzoquinones
HSP70 Heat-Shock Proteins
HSP90 Heat-Shock Proteins
Lactams, Macrocyclic
RNA, Messenger
RNA, Neoplasm
Retroviridae Proteins, Oncogenic
Rifabutin
tanespimycin
Oncogene Protein v-akt
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-raf