Abstract 475: uPAR and cathepsin B knockdown inhibits radiation-induced PKC integrated integrin signaling to the cytoskeleton and migration of glioma initiating cells
2012
Glioblastoma (GBM) remains one of the most fatal and least successfully treated solid tumors. It is evident that some cancer cells with stem cell properties (known as glioma initiating cells; GICs) survive conventional treatments and are involved in the recurrence of tumors. In the present study, CD133+ GICs were isolated from established U251 and 5310 glioma cell lines and subjected to radiation and transfection with shRNA against uPAR and cathepsin B so that we could study the events related to cell migration. Simultaneous downregulation of uPAR and cathepsin B (pUC) caused the disruption of radiation-induced complex formation of pPKC∈/α:integrinβ1 and PKC∈:integrinβ1 in glioma cells as well as in GICs as was observed by immunoprecipitation analysis. Further, pUC treatment also inhibited the PKC/integrin signal through FAK by disintegrating the association of FAK and the cytoskeletal molecules vinculin and α-actinin. It was also observed that inhibition of radiation-induced ERK phosphorylation by pUC directed a negative feedback mechanism over the FAK signaling molecules that led to an extensive reduction in the cytoskeletal organization, and thereby generating a migratory arrest. Further confirmation was obtained by treating the cells with U0126 (10 µM), a MEK inhibitor, and rottlerin (200 µM), a PKC inhibitor. pUC treatment efficiently inhibited the co-localization of pPKC∈/α/integrinβ1, PKC∈/integrinβ1, FAK/vinculin and FAK/α-actinin in the brain tumor sections of mice implanted with glioma cells and GICs. In conclusion, shRNA-mediated knockdown of uPAR and cathepsin B could be an effective treatment strategy for controlling highly invasive glioma cells and treatment-resistant glioma initiating cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 475. doi:1538-7445.AM2012-475
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