Antiproliferative effect of the HSP90 inhibitor NVP-AUY922 is determined by the expression of PTEN in esophageal cancer.

Abstract

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.

• Authors: Xiao-Hong Bao, Munenori Takaoka, Hui-Fang Hao, Takuya Fukazawa, Tomoki Yamatsuji, Kazufumi Sakurama, Nagio Takigawa, Motowo Nakajima, Toshiyoshi Fujiwara, Yoshio Naomoto
• Journal: Oncology reports (Oncol Rep) Vol. 29 Issue 1 Pg. 45-50 (Jan 2013) ISSN: 1791-2431 [Electronic] Greece
• PMID: 23064324 (Publication Type: Journal Article)

Chemical References

• 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
• HSP90 Heat-Shock Proteins
• Isoxazoles
• RNA, Small Interfering
• Resorcinols
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Apoptosis (drug effects)
• Blotting, Western
• Carcinoma, Squamous Cell (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Esophageal Neoplasms (drug therapy, metabolism, pathology)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Isoxazoles (pharmacology)
• PTEN Phosphohydrolase (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Small Interfering (genetics)
• Resorcinols (pharmacology)
• Tumor Cells, Cultured