TAE226, a dual inhibitor for FAK and IGF-IR, has inhibitory effects on mTOR signaling in esophageal cancer cells.
Esophageal cancer is one of the most aggressive cancers in the world. Novel preventive and therapeutic strategies tend to target the key molecules involved in the signaling transduction pathways for cell growth. It is known that FAK and mTOR are important controllers of cell growth. TAE226, a novel small molecule compound, is a potent ATP competitive inhibitor of FAK and IGF-IR. TAE226 can block FAK and IGF-IR signaling pathways. The purpose of this study was to explore the inhibitory effects on mTOR signaling and the mechanism of cell growth suppression by TAE226. We examined the expression of mTOR and S6 in esophageal cancer cells (SEG-1) and normal esophageal epithelial cells (KOB-13) and the efficacy of TAE226 against SEG-1 cells. mTOR and S6 were overexpressed in SEG-1 cells compared with KOB-13 cells. TAE226 inhibited the expression of mTOR, Akt, p70S6K and S6 as well as the phosphorylation of mTOR (Ser2448), Akt (Ser473), p70S6K (Thr389) and S6 (Ser240/244). As a result, TAE226 induced a dose-dependent decrease in cell growth (number) and damage in the cell shape. Together, these data show that TAE226 has potent inhibitory effects on mTOR signaling and esophageal cancer cell growth indicating that TAE226 has potential application in esophageal cancer treatment.
Wang
Zhi Gang
ZG
College of Life Science, Inner Mongolia University, The Key Laboratory of Mammal Reproductive Biology and Biotechnology, Ministry of Education, Huhhot 010021, P.R. China.
Fukazawa
Takuya
T
Nishikawa
Toshio
T
Watanabe
Nobuyuki
N
Sakurama
Kazufumi
K
Motoki
Takayuki
T
Takaoka
Munenori
M
Hatakeyama
Shinji
S
Omori
Osamu
O
Ohara
Toshiaki
T
Tanabe
Shunsuke
S
Fujiwara
Yasuhiro
Y
Shirakawa
Yasuhiro
Y
Yamatsuji
Tomoki
T
Tanaka
Noriaki
N
Naomoto
Yoshio
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors
D000970:Antineoplastic Agents; D009025:Morpholines; C524632:TAE226; D011494:Protein Kinases; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases