title: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) promotes glioblastoma cell chemotaxis via Lyn activation.
abstract: The long-term survival of patients with glioblastoma is compromised by the proclivity for local invasion into the surrounding normal brain, escaping surgical resection and contributing to therapeutic resistance. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, can stimulate glioma cell invasion via binding to fibroblast growth factor-inducible 14 (Fn14) and subsequent activation of the Rho guanosine triphosphatase family member Rac1. Here, we demonstrate that TWEAK acts as a chemotactic factor for glioma cells, a potential process for driving cell invasion into the surrounding brain tissue. TWEAK exposure induced the activation of Src family kinases (SFKs), and pharmacologic suppression of SFK activity inhibited TWEAK-induced chemotactic migration. We employed a multiplexed Luminex assay and identified Lyn as a candidate SFK activated by TWEAK. Depletion of Lyn suppressed TWEAK-induced chemotaxis and Rac1 activity. Furthermore, Lyn gene expression levels increase with primary glioma tumor grade and inversely correlate with patient survival. These results show that TWEAK-induced glioma cell chemotaxis is dependent upon Lyn kinase function and, thus, provides opportunities for therapeutic targeting of this deadly disease.
authors: Cancer and Cell Biology Division, The Translational Genomics Research Institute (TGen), Phoenix, AZ, USA and.
authors: Harshil D
authors: HD
authors: Dhruv
authors: Timothy G
authors: TG
authors: Whitsett
authors: Nathan M
authors: NM
authors: Jameson
authors: Falak
authors: F
authors: Patel
authors: Jeffrey A
authors: JA
authors: Winkles
authors: Michael E
authors: ME
authors: Berens
authors: Nhan L
authors: NL
authors: Tran
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002465:Cell Movement; D002633:Chemotaxis / Q000502:physiology*; D000074049:Cytokine TWEAK; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017208:Rats, Wistar; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000074049:Cytokine TWEAK; C107953:RAC1 protein, human; C109743:TNFSF12 protein, human; D048069:Tumor Necrosis Factors; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D020830:rac1 GTP-Binding Protein
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