The TWEAK Receptor Fn14 Is an Src-Inducible Protein and a Positive Regulator of Src-Driven Cell Invasion.
The TNF receptor superfamily member Fn14 (TNFRSF12A) is the sole signaling receptor for the proinflammatory cytokine TWEAK (TNFSF12).
Fn14 engagement stimulates multiple signal transduction pathways, including the NF-κB pathway, and this triggers important cellular processes (e.g., growth, differentiation, migration, and invasion). The TWEAK-Fn14 axis is thought to be a major physiologic mediator of tissue repair after acute injury. Various studies have revealed that Fn14 is highly expressed in many solid tumor types, and that Fn14 signaling may play a role in tumor growth and metastasis. Previously, it was shown that Fn14 levels are frequently elevated in non-small cell lung cancer (NSCLC) tumors and cell lines that exhibit constitutive EGFR phosphorylation (activation). Furthermore, elevated Fn14 levels increased NSCLC cell invasion in vitro and lung metastatic tumor colonization in vivo. The present study reveals that EGFR-mutant NSCLC cells that express high levels of Fn14 exhibit constitutive activation of the cytoplasmic tyrosine kinase Src, and that treatment with the Src family kinase (SFK) inhibitor dasatinib decreases Fn14 gene expression at both the mRNA and protein levels. Importantly, siRNA-mediated depletion of the SFK member Src in NSCLC cells also decreases Fn14 expression. Finally, expression of the constitutively active v-Src oncoprotein in NIH 3T3 cells induces Fn14 gene expression, and NIH 3T3/v-Src cells require Fn14 expression for full invasive capacity.


CONCLUSIONS
These results indicate that oncogenic Src may contribute to Fn14 overexpression in solid tumors, and that Src-mediated cell invasion could potentially be inhibited with Fn14-targeted therapeutics.
Department of Surgery, Center for Vascular and Inflammatory Diseases, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland.
Emily
E
Cheng
Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona.
Timothy G
TG
Whitsett
Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona.
Nhan L
NL
Tran
Department of Surgery, Center for Vascular and Inflammatory Diseases, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland. jwinkles@som.umaryland.edu.
Jeffrey A
JA
Winkles
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D000069439:Dasatinib / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009154:Mutation; D009361:Neoplasm Invasiveness; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000378:metabolism*; D000074050:TWEAK Receptor; D019061:src-Family Kinases / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C512478:EGFR protein, human; D066246:ErbB Receptors; D000081247:CSK Tyrosine-Protein Kinase; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases; C000631346:CSK protein, human; D000069439:Dasatinib