uPAR and cathepsin B-mediated compartmentalization of JNK regulates the migration of glioma-initiating cells.
In the present study, we investigated the effect of simultaneous downregulation of uPAR and cathepsin B (pUC), alone or in combination with radiation, on JNK-MAPK signaling pathway in regulating the migration of non-GICs (glioma-initiating cells) and GICs. The increase in the expression of p-JNK with pUC treatment was mostly localized to nucleus whereas increase in the expression of p-JNK with radiation and overexpression of uPAR and cathepsin B was confined to cytoplasm of the cells. Depletion of cytosolic p-JNK with pUC treatment inhibited migration by downregulating the expression of the adapter proteins of the focal adhesion complex. We also observed that knockdown of uPAR and cathepsin B regulated the Ras-Pak-1 pathway to induce the translocation of p-JNK from cytosol to nucleus. In control cells, Pak-1 served as a functional inhibitor for MEKK-1, which inhibits the complex formation of MEKK-1 and p-JNK and thus inhibits the translocation of this complex into nucleus. Hence, we conclude that glioma cells utilize the availability of cytosolic p-JNK in driving the cells towards migration. Finally, treating the cells with pUC alone or in combination with radiation induced the translocation of the MEKK-1-p-JNK complex from cytosol to nucleus, thereby inhibiting the migration of glioma cells.
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.
Kiranmai
K
Alapati
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.
Divya
D
Kesanakurti
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA; Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.
Jasti S
JS
Rao
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA. Electronic address: rdasari@uic.edu.
Venkata Ramesh
VR
Dasari
D000818:Animals; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D002467:Cell Nucleus / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D021381:Protein Transport; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
D055293:Receptors, Urokinase Plasminogen Activator; D048670:MAP Kinase Kinase 4; D002401:Cathepsin B