c-Src and neural Wiskott-Aldrich syndrome protein (N-WASP) promote low oxygen-induced accelerated brain invasion by gliomas.
Malignant gliomas remain associated with poor prognosis and high morbidity because of their ability to invade the brain; furthermore, human gliomas exhibit a phenotype of accelerated brain invasion in response to anti-angiogenic drugs. Here, we study 8 human glioblastoma cell lines; U251, U87, D54 and LN229 show accelerated motility in low ambient oxygen. Src inhibition by Dasatinib abrogates this phenotype. Molecular discovery and validation studies evaluate 46 molecules related to motility or the src pathway in U251 cells. Demanding that the molecular changes induced by low ambient oxygen are reversed by Dasatinib in U251 cells, identifies neural Wiskott-Aldrich syndrome protein (NWASP), Focal adhesion Kinase (FAK), [Formula: see text]-Catenin, and Cofilin. However, only Src-mediated NWASP phosphorylation distinguishes the four cell lines that exhibit enhanced motility in low ambient oxygen. Downregulating c-Src or NWASP by RNA interference abrogates the low-oxygen-induced enhancement in motility by in vitro assays and in organotypic brain slice cultures. The findings support the idea that c-Src and NWASP play key roles in mediating the molecular pathogenesis of low oxygen-induced accelerated brain invasion by gliomas.
Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Zhuo
Z
Tang
Lita M
LM
Araysi
Hassan M
HM
Fathallah-Shaykh
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D000860:Hypoxia; D051379:Mice; D009361:Neoplasm Invasiveness; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human