Antiproliferative effect of the HSP90 inhibitor NVP-AUY922 is determined             by the expression of PTEN in esophageal cancer.
Heat shock protein 90 (HSP90), a molecular chaperone, has provoked great             interest as a promising molecular target for cancer treatment, due to its involvement             in regulating the conformation, stability and functions of key oncogenic proteins.             At present, a variety of chemical compounds targeting HSP90 have been developed             and have shown convincing anti-neoplastic activity in various preclinical tumor             models. The aim of our study was to evaluate the antitumor effects of a novel             HSP90 inhibitor, NVP-AUY922, in esophageal squamous cancer cells (ESCC). Four             ESCC cell lines (TE-1, TE-4, TE-8, TE-10) were examined. NVP-AUY922 potently inhibited             the proliferation of ESCC, particularly in PTEN-null TE-4 cells with a 2-3 times             lower IC50 than the other three cell lines. Western blot analysis showed that             PTEN-null TE-4 cells exhibited higher AKT and ERK activity, which contribute to             cell proliferation and survival. NVP-AUY922 significantly suppressed the activity             of AKT and ERK in TE-4 but not in PTEN-proficient TE-10 cells. Genetic modification             experiments demonstrated that the sensitivity to NVP-AUY922 was decreased by exogenous             transduction of PTEN in TE-4 and increased by silencing PTEN expression in intact             PTEN-expressing TE-10, suggesting that the expression of PTEN may be associated             with cell sensitivity in HSP90 inhibition. Furthermore, the enhanced activity             of AKT in PTEN-silenced TE-10 was more easily suppressed by NVP-AUY922. Collectively,             NVP-AUY922 exhibits a strong antiproliferative effect, revealing its potential             as a novel therapeutic alternative to current ESCC treatment. The effect may be             improved further by impeding PTEN expression.
Department of Gastroenterological Surgery, Transplant and Surgical Oncology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Xiao-Hong
XH
Bao
Munenori
M
Takaoka
Hui-Fang
HF
Hao
Takuya
T
Fukazawa
Tomoki
T
Yamatsuji
Kazufumi
K
Sakurama
Nagio
N
Takigawa
Motowo
M
Nakajima
Toshiyoshi
T
Fujiwara
Yoshio
Y
Naomoto
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects*; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012118:Resorcinols / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D034741:RNA, Small Interfering; D012118:Resorcinols; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human