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A novel low‐molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth
Author(s) -
Shi Qing,
Hjelmeland Anita B.,
Keir Stephen T.,
Song Linhua,
Wickman Sarah,
Jackson Dowdy,
Ohmori Osamu,
Bigner Darell D.,
Friedman Henry S.,
Rich Jeremy N.
Publication year - 2007
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20297
Subject(s) - focal adhesion , biology , ptk2 , glioma , microbiology and biotechnology , cancer research , tyrosine kinase , protein kinase b , signal transduction , tyrosine phosphorylation , integrin , cell adhesion , ribosomal s6 kinase , cell growth , phosphorylation , receptor tyrosine kinase , cell , p70 s6 kinase 1 , protein kinase a , biochemistry , mitogen activated protein kinase kinase
Glioblastomas are highly lethal cancers that resist current therapies. Novel therapies under development target molecular mechanisms that promote glioblastoma growth. In glioblastoma patient specimens, the non‐receptor tyrosine kinase focal adhesion kinase (FAK) is overexpressed. Upon growth factor receptor stimulation or integrin engagement, FAK is activated by phosphorylation on critical tyrosine residues. Activated FAK initiates a signal transduction cascade which promotes glioma growth and invasion by increasing cellular adhesion, migration, invasion, and proliferation. We find that human glioma cell lines express different levels of total FAK protein and activating phosphorylation of tyrosine residues Tyr397, Tyr861, and Tyr925. As all glioma cell lines examined expressed phosphorylated FAK, we examined the efficacy of a novel low‐molecular weight inhibitor of FAK, TAE226, against human glioma cell lines. TAE226 inhibited the phosphorylation of FAK as well as the downstream effectors AKT, extracellular signal‐related kinase, and S6 ribosomal protein in multiple glioma cell lines. TAE226 induced a concentration‐dependent decrease in cellular proliferation with an associated G 2 cell cycle arrest in every cell line and an increase in apoptosis in a cell‐line‐specific manner. TAE226 also decreased glioma cell adhesion, migration, and invasion through an artificial extracellular matrix. Together, these data demonstrate the potential benefit of TAE226 for glioma therapy. © 2007 Wiley‐Liss, Inc.