Inhibition of Hsp90 leads to cell cycle arrest and apoptosis in human malignant pleural mesothelioma.
BACKGROUND
Heat shock protein 90 (Hsp90) is an abundant molecular chaperone that mediates the maturation and stability of a variety of proteins associated with the promotion of cell growth and survival. Inhibition of Hsp90 function leads to proteasomal degradation of its mis-folded client proteins. Recently, Hsp90 has emerged as being of prime importance to the growth and survival of cancer cells and its inhibitors have already been used in phase I and II clinical trials.


METHODS
We investigated how 17-allylamino-17-demethoxygeldanamycin (17-AAG), a small molecule inhibitor of Hsp90, is implicated in human malignant pleural mesothelioma (MM).


RESULTS
We found that 17-AAG led to significant G1 or G2/M cell cycle arrest, inhibition of cell proliferation, and decrease of AKT, AKT1, and survivin expression in all human malignant pleural mesothelioma cell lines examined. We also observed significant apoptosis induction in all MM cell lines treated with 17-AAG. Furthermore, 17-AAG induced apoptosis in freshly cultured primary MM cells and caused signaling changes identical to those in 17-AAG treated MM cell lines.


CONCLUSIONS
These results suggest that Hsp90 is strongly associated with the growth and survival of MM and that inhibition of Hsp90 may have therapeutic potential in the treatment of MM.
Okamoto
Junichi
J
Thoracic Oncology Laboratory, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.
Mikami
Iwao
I
Tominaga
Yuichi
Y
Kuchenbecker
Kristopher M
KM
Lin
Yu-Ching
YC
Bravo
Dawn T
DT
Clement
Genevieve
G
Yagui-Beltran
Adam
A
Ray
M Roshni
MR
Koizumi
Kiyoshi
K
He
Biao
B
Jablons
David M
DM
D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077022:Survivin; D014407:Tumor Cells, Cultured
C107489:BIRC5 protein, human; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D051034:Inhibitor of Apoptosis Proteins; D047029:Lactams, Macrocyclic; D008869:Microtubule-Associated Proteins; D000077022:Survivin; C112765:tanespimycin; D051057:Proto-Oncogene Proteins c-akt