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.
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
Clarke
P A
PA
Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, E Block, 15, Cotswold Road, Sutton, Surrey, SM2 5NG, UK.
Hostein
I
I
Banerji
U
U
Stefano
F D
FD
Maloney
A
A
Walton
M
M
Judson
I
I
Workman
P
P
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016227:Benzoquinones; D015153:Blotting, Western; D003110:Colonic Neoplasms; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D047029:Lactams, Macrocyclic; D008214:Lymphocytes / Q000187:drug effects; D051058:Oncogene Protein v-akt; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis / Q000378:metabolism; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D015682:Retroviridae Proteins, Oncogenic; D017828:Rifabutin; C112765:tanespimycin; D051058:Oncogene Protein v-akt; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf