Munenori Takaoka    Department   Kawasaki Medical School  Kawasaki Medical School, Department of General Surgery,    Position   Associate Professor
Language	English
Title	Inhibition of mammalian target of rapamycin(mTOR)signaling by Temsirolimus as a potential therapeutic strategy for esophageal cancer treatment.
Conference	American Association for Cancer Reserch 102nd ANNUAL MEETING
Conference Type	International society and overseas society
Presentation Type	Poster notice
Publisher and common publisher	◎Munenori Takaoka, Toshio Nishikawa, Toshiaki Ohara, Yasuko Tomono, Yasuhiro Fujiwara, Yasuhiro Shirakawa, Hitoshi Nagatsuka, Takuya Fukazawa, Tomoki Yamatsuji, Xiaohong Bao, Huifang Hao, Kaori Shigemitsu, Ichiro Morita, Toshiyoshi Fujiwara, Yoshio Naomoto
Date	2011/04/04
Venue (city and name of the country)	Florida,USA
Summary	[Background] Heat shock protein90(HSP90) has provoked great interest as a promising molecular target for cancer treatment, since it is involved in regulating the conformation, stability and functions of key oncogenic proteins. [Materials and Methods]esophageal cancer cells(TE-1, TE-4, TE-8, TE-10), Gastric cancer cells(NUGC-3, NUGC-3/IL), pancreatic cancer cells(PANC-1, MIAPACA-2, Bxpc3) and mutant c-kit-driven lymphocytes(Ba/F3-Kofi, Ba/F3-K642, Ba/F3-820Mz), mimicking gastrointestinal stromal tumor cells, were examined. WST assay was conducted to assess the anti-proliferation effects of NVP-AUY922. The activity of cell growth-related molecules were investigated by western blot Genetic modification using siRNA and expression vector were applied for silencing and overexpression of PTEN, respectively. [Results]NVP-AUY922 potently inhibits the proliferation of human cancer cell lines, regardless of 5-FU resistance or c-Kit mutation, by which the sensitivity to imatinib can be affected. PTEN-null TE-4 cells exhibited more sensitivity to NVP-AUY922. The sensitivity to NVP-AUY922 was increased by silencing PTEN expression in intact PTEN expressing TE-10 cells and decreased by exogenous transduction of PTEN in TE-4 cells. Furthermore, NVP-AUY922 significantly inhibited the activity of AKT and ERK in TE-4 cells, but not in TE-10 cells. [Conclusion]NVP-AUY922 exhibited strong cytotoxicity against most of the cancer cells, including some anticancer drug-resistant cells. The expression status of PTEN determines the sensitivity to HSP90 inhibitor.