Hsp90 inhibitors cause G2/M arrest associated with the reduction of Cdc25C and Cdc2 in lung cancer cell lines.
OBJECTIVE
Hsp90, a molecular chaperone, is involved in folding, assembly, maturation, and stabilization of the client proteins which regulate survival of cancer cells, and thus Hsp90 inhibitors may be potential molecular targeting agents for cancer treatment. We investigated whether Hsp90 inhibitors have therapeutic value in lung cancer.


METHODS
First, expression levels of Hsp90 in lung cancer cells were examined by western blotting and immunohistochemical analyses. Next, the effect of Hsp90 inhibitors, geldanamycin and 17-allylaminogeldanamycin (17-AAG), on lung cancer cell growth was examined.


RESULTS
Remarkable high expression of Hsp90 protein in lung cancer cell lines and a more intense signal for Hsp90 by immunohistochemistry in males, patients with smoking index over 600, and squamous cell carcinoma were observed. Both Hsp90 inhibitors dose dependently inhibited the growth of lung cancer cell lines and induced G2/M arrest concomitant with decreased protein levels of Cdc25C and Cdc2. Moreover, combination of an Hsp90 inhibitor and irradiation had an additive effect on cell growth inhibition and reduction of Cdc25C and Cdc2 protein levels.


CONCLUSIONS
Hsp90 inhibitor is thus a therapeutic tool for lung cancer based on its target proteins, which are involved in tumor progression and antiproliferative activity in lung cancer cells.
Senju
Megumi
M
Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan.
Sueoka
Naoko
N
Sato
Akemi
A
Iwanaga
Kentaro
K
Sakao
Yukinori
Y
Tomimitsu
Shinji
S
Tominaga
Masaki
M
Irie
Koji
K
Hayashi
Shinichiro
S
Sueoka
Eisaburo
E
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000096:biosynthesis / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000187:drug effects*; D045744:Cell Line, Tumor; D005260:Female; D016195:G2 Phase / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D020687:cdc25 Phosphatases / Q000096:biosynthesis / Q000187:drug effects*
D016227:Benzoquinones; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D016203:CDC2 Protein Kinase; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases