Gene and protein expression profiling of human ovarian cancer cells treated with the heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin.
The promising antitumor activity of 17-allylamino-17-demethoxygeldanamycin (17AAG) results from inhibition of the molecular chaperone heat shock protein 90 (HSP90) and subsequent degradation of multiple oncogenic client proteins. Gene expression microarray and proteomic analysis were used to profile molecular changes in the A2780 human ovarian cancer cell line treated with 17AAG. Comparison of results with an inactive analogue and an alternative HSP90 inhibitor radicicol indicated that increased expression of HSP72, HSC70, HSP27, HSP47, and HSP90beta at the mRNA level were on-target effects of 17AAG. HSP27 protein levels were increased in tumor biopsies following treatment of patients with 17AAG. A group of MYC-regulated mRNAs was decreased by 17AAG. Of particular interest and novelty were changes in expression of chromatin-associated proteins. Expression of the heterochromatin protein 1 was increased, and expression of the histone acetyltransferase 1 and the histone arginine methyltransferase PRMT5 was decreased by 17AAG. PRMT5 was shown to be a novel HSP90-binding partner and potential client protein. Cellular protein acetylation was reduced by 17AAG, which was shown to have an antagonistic interaction on cell proliferation with the histone deacetylase inhibitor trichostatin A. This mRNA and protein expression analysis has provided new insights into the complex molecular pharmacology of 17AAG and suggested new genes and proteins that may be involved in response to the drug or be potential biomarkers of drug action.
Maloney
Alison
A
Haddow Laboratories, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Surrey, United Kingdom.
Clarke
Paul A
PA
Naaby-Hansen
Soren
S
Stein
Rob
R
Koopman
Jens-Oliver
JO
Akpan
Akunna
A
Yang
Alice
A
Zvelebil
Marketa
M
Cramer
Rainer
R
Stimson
Lindsay
L
Aherne
Wynne
W
Banerji
Udai
U
Judson
Ian
I
Sharp
Swee
S
Powers
Marissa
M
deBilly
Emmanuel
E
Salmons
Joanne
J
Walton
Michael
M
Burlingame
Al
A
Waterfield
Michael
M
Workman
Paul
P
D000107:Acetylation; D016227:Benzoquinones / Q000494:pharmacology*; D001706:Biopsy; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D018942:Macrolides / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011496:Protein Methyltransferases / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases; D040901:Proteomics
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018942:Macrolides; D009363:Neoplasm Proteins; C112765:tanespimycin; D011496:Protein Methyltransferases; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; C035359:monorden