uPAR and cathepsin B knockdown inhibits radiation-induced PKC integrated             integrin signaling to the cytoskeleton of glioma-initiating cells.
Despite advances in radiotherapeutic and chemotherapeutic techniques and             aggressive surgical resection, the prognosis of glioblastoma patients is dismal.             Accumulation of evidence indicates that some cancer cells survive even the most             aggressive treatments, and these surviving cells, which are resistant to therapy             and are perhaps essential for the malignancy, may be cancer stem cells. The CD133             surface marker is commonly used to isolate these extremely resistant glioma-initiating             cells (GICs). In the present study, GICs which tested positive for the CD133 marker             (CD133+) were isolated from both the established U251 cell line and the 5310 xenograft             glioma cell line to study the events related to the molecular pathogenesis of             these cells. Simultaneous down-regulation of uPAR and cathepsin B by shRNA (pUC)             treatment caused the disruption of radiation-induced complex formation of pPKC θ/δ,             integrin β1 and PKC ζ, integrin β1 in glioma cells. Further, pUC treatment inhibited             PKC/integrin signaling via FAK by causing disassociation of FAK and the cytoskeletal             molecules vinculin and α-actinin. Also, we observed the inhibition of ERK phosphorylation.             This inhibition was mediated by pUC and directed a negative feedback mechanism             over the FAK signaling molecules, which led to an extensive reduction in the signal             for cytoskeletal organization generating migratory arrest. Altogether, it can             be hypothesized that knockdown of uPAR and cathepsin B using shRNA is an effective             strategy for controlling highly invasive glioma cells and extremely resistant             glioma-initiating cells.
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL 61605, USA.
Kiranmai
K
Alapati
Sreelatha
S
Gopinath
Rama Rao
RR
Malla
Venkata Ramesh
VR
Dasari
Jasti S
JS
Rao
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology; D002401:Cathepsin B / Q000235:genetics* / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D003599:Cytoskeleton / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism / Q000502:physiology; D015870:Gene Expression / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000473:pathology*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000528:radiation effects; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000098:Acetophenones; D000943:Antigens, Differentiation; D001578:Benzopyrans; D015816:Cell Adhesion Molecules, Neuronal; D019012:Integrin beta1; D016023:Integrins; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; C085746:rottlerin; D011493:Protein Kinase C; C533912:CTSB protein, human; D002401:Cathepsin B