The novel angiogenic inhibitor, angiocidin, induces differentiation of monocytes to macrophages.
We previously showed that angiocidin, a tumor and vascular associated protein, is a potent inhibitor of angiogenesis and tumor growth. Angiocidin is a multidomain protein that exerts its antiangiogenic activity through multiple mechanisms, including effects on cell matrix interaction. Here, we describe another activity of angiocidin that may contribute to its antitumor activity. We show that angiocidin activates monocytes to secrete a mixture of proinflammatory cytokines and induces them to differentiate into macrophage-like cells. Using the monocytic cell line THP-1, we show that angiocidin induces the cells to become adherent and phagocytic, express macrophage markers, and secrete matrix metalloproteinase-9. Microarray analysis of control and angiocidin-treated THP-1 cells revealed that angiocidin up-regulated p105/p50, p100/p52, and rel B, components of the nuclear factor-kappaB (NF-kappaB) pathway. We confirmed the microarray data and showed that angiocidin induced phosphorylation of I kappa beta, p50, and p65 and translocation of p50 and p65 to the nucleus. We also showed that angiocidin activated up-stream mediators of NF-kappaB, such as the mitogen-activated protein kinase (MAPK) pathway and phosphoinositide-3 kinase (PI3K). Blockage of NF-kappaB and MAPK activation with small molecule inhibitors completely prevented angiocidin-mediated secretion of cytokines from THP-1 cells, but did not inhibit their adhesive phenotype. Blocking PI3K inhibited both secretion of cytokines, as well as the adhesive phenotype. These data suggest that angiocidin activates monocytes to secrete cytokines and differentiates them to a macrophage-like phenotype through at least two pathways mediated by MAPK and NF-kappaB, as well as PI3K.
Gaurnier-Hausser
Anita
A
Department of Biology, Temple University, Philadelphia, Pennsylvania 19122, USA.
Rothman
Vicki L
VL
Dimitrov
Svetoslav
S
Tuszynski
George P
GP
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D002352:Carrier Proteins / Q000494:pharmacology*; D002448:Cell Adhesion; D002454:Cell Differentiation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D009000:Monocytes / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D010587:Phagocytosis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D016601:RNA-Binding Proteins
D020533:Angiogenesis Inhibitors; D002352:Carrier Proteins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D016601:RNA-Binding Proteins; C498506:PSMD4 protein, human