title: Suppression of uPA and uPAR blocks radiation-induced MCP-1 mediated recruitment of endothelial cells in meningioma.
abstract: Chemokines play a vital role in recruiting various cell types in the process of tissue repair. Radiation, a major therapeutic modality in cancer treatment, has been described to induce inflammatory response that might lead to the expression of several chemokines. In the present study, we investigated the mechanism of monocyte chemoattractant protein-1 (MCP-1) induction by radiation in meningioma cell lines and the paracrine effect on human microvascular endothelial cells (HMEC). After radiation, meningioma cell lines (IOMM Lee and SF-3061) showed an increased expression of MCP-1. In addition, irradiated meningioma cancer cell conditioned medium (CM) showed an increased ability to attract HMEC and to stimulate MCP-1-induced protein (MCPIP), VEGF and angiogenin expression in HMEC. This chemotactic activity and angiogenic stimulator effect on HMEC were almost abrogated by depleting MCP-1 from the irradiated cancer cell CM. Further, inhibition of either ERK activation/expression or NF-κB nuclear translocation hindered radiation-induced MCP-1 expression in both meningioma cell lines. Further, supplementing cancer cells with exogenous ATF-uPA (with and without radiation) activated ERK phosphorylation, nuclear translocation of the NF-κB p65 sub-unit (Rel-A), and MCP-1 expression. Downregulation of uPA and uPAR, simultaneously by transfecting the cancer cells with bi-cistronic siRNA-expressing plasmid (pU) inhibited radiation-induced ERK activation, nuclear translocation of Rel-A, NF-κB DNA binding activity, and MCP-1 expression. In addition, pU-transfected cancer cells (with or without radiation) reduced radiation-induced MCP-1 and blocked the recruitment of other cell types during the inflammatory process induced by radiation both in in vitro and in vivo conditions.
authors.affiliation: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, One Illini Drive, Peoria, IL 61605, USA.
authors.forename: Arun Kumar
authors.initials: AK
authors.lastname: Nalla
authors.forename: Venkateswara Rao
authors.initials: VR
authors.lastname: Gogineni
authors.forename: Reshu
authors.initials: R
authors.lastname: Gupta
authors.forename: Dzung H
authors.initials: DH
authors.lastname: Dinh
authors.forename: Jasti S
authors.initials: JS
authors.lastname: Rao
mesh_terms: D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism* / Q000528:radiation effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008577:Meningeal Neoplasms / Q000378:metabolism* / Q000532:radiotherapy; D008579:Meningioma / Q000378:metabolism* / Q000532:radiotherapy; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011839:Radiation, Ionizing; D055293:Receptors, Urokinase Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D012260:Ribonucleases; D051996:Transcription Factor RelA / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D016328:NF-kappa B; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; D051996:Transcription Factor RelA; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D048049:Extracellular Signal-Regulated MAP Kinases; D012260:Ribonucleases; C510646:ZC3H12A protein, human; C046366:angiogenin; D012259:Ribonuclease, Pancreatic; D014568:Urokinase-Type Plasminogen Activator