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

Xiao Hong Bao, Munenori Takaoka, Hui Fang Hao, Takuya Fukazawa, Tomoki Yamatsuji, Kazufumi Sakurama, Nagio Takigawa, Motowo Nakajima, Toshiyoshi Fujiwara, Yoshio Naomoto

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8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)45-50
Number of pages6
JournalOncology reports
Volume29
Issue number1
DOIs
Publication statusPublished - Jan 1 2013

Keywords

  • Esophageal cancer
  • Heat shock protein 90
  • NVP-AUY922
  • PTEN

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Bao, X. H., Takaoka, M., Hao, H. F., Fukazawa, T., Yamatsuji, T., Sakurama, K., Takigawa, N., Nakajima, M., Fujiwara, T., & Naomoto, Y. (2013). Antiproliferative effect of the HSP90 inhibitor NVP-AUY922 is determined by the expression of PTEN in esophageal cancer. Oncology reports, 29(1), 45-50. https://doi.org/10.3892/or.2012.2074