title: Transcriptional profiling of GBM invasion genes identifies effective inhibitors of the LIM kinase-Cofilin pathway.
abstract: Malignant gliomas are highly proliferative and invasive neoplasms where total surgical resection is often impossible and effective local radiation therapy difficult. Consequently, there is a need to develop a greater understanding of the molecular events driving invasion and to identify novel treatment targets. Using microarray analysis comparing normal brain samples and mesenchymal glioblastoma multiforme (GBM), we identified over 140 significant genes involved in cell migration and invasion. The cofilin (CFL) pathway, which disassembles actin filaments, was highly up-regulated compared to normal brain. Up-regulation of LIM domain kinase 1 and 2 (LIMK1/2), that phosphorylates and inactivates cofilin, was confirmed in an additional independent data set comparing normal brain to GBM. We identified and utilized two small molecule inhibitors BMS-5 and Cucurbitacin I directed against the cofilin regulating kinases, LIMK1 and LIMK2, to target this pathway. Significant decreases in cell viability were observed in glioma cells treated with BMS-5 and Cucurbitacin I, while no cytotoxic effects were seen in normal astrocytes that lack LIMK. BMS-5 and Cucurbitacin I promoted increased adhesion in GBM cells, and decreased migration and invasion. Collectively, these data suggest that use of LIMK inhibitors may provide a novel way to target the invasive machinery in GBM.
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, ON, Canada. Department of Neurological Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.
authors.forename: Jun-Bum
authors.initials: JB
authors.lastname: Park
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Sameer
authors.initials: S
authors.lastname: Agnihotri
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Golbourn
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Kelsey C
authors.initials: KC
authors.lastname: Bertrand
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Amanda
authors.initials: A
authors.lastname: Luck
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Nesrin
authors.initials: N
authors.lastname: Sabha
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Smith
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Sara
authors.initials: S
authors.lastname: Byron
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, ON, Canada. Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Canada.
authors.forename: Gelareh
authors.initials: G
authors.lastname: Zadeh
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Sidney
authors.initials: S
authors.lastname: Croul
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Berens
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, ON, Canada. Department of Surgery, University of Toronto, Toronto ON, Canada.
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
mesh_terms: D001921:Brain / Q000473:pathology; D053148:Caspase 3 / Q000032:analysis; D053179:Caspase 7 / Q000032:analysis; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D051338:Cofilin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018628:Gene Dosage / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D054461:Lim Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009361:Neoplasm Invasiveness / Q000235:genetics*; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D014315:Triterpenes / Q000494:pharmacology
chemical_list: D051338:Cofilin 1; D034741:RNA, Small Interfering; D014315:Triterpenes; C515892:LIMK1 protein, human; C102895:LIMK2 protein, human; D054461:Lim Kinases; D053148:Caspase 3; D053179:Caspase 7; C038106:cucurbitacin I