title: A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth.
abstract: 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.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Shi
authors.forename: Anita B
authors.initials: AB
authors.lastname: Hjelmeland
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: Linhua
authors.initials: L
authors.lastname: Song
authors.forename: Sarah
authors.initials: S
authors.lastname: Wickman
authors.forename: Dowdy
authors.initials: D
authors.lastname: Jackson
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohmori
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
mesh_terms: D017304:Annexin A5 / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy; D006801:Humans; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D014443:Tyrosine / Q000737:chemistry
chemical_list: D017304:Annexin A5; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D014443:Tyrosine; D051416:Focal Adhesion Protein-Tyrosine Kinases