<<<<< << <<< er" content="American Association for Cancer Research" /> up/volpage/13/1019?iss=5" /> GF, and interleukin-6 (IL-6). Moreover, GAGF, and interleukin-6 (IL-6). Moreover, GALR2 activated smalGF, and interleukin-6 (IL-6). Moreover, GALR2 activated small-GTP-protein, RAP1B,GF, and interleukin-6 (IL-6). Moreover, GALR2 activated small-GTP-protein, RAP1B, thereby inducing p38-mediated inactivationGF, and interleukin-6 (IL-6). Moreover, GALR2 activated small-GTP-protein, RAP1B, thereby inducing p38-mediated inactivation of tristetraprolin (TTP), which functions to destabilize cytokine transcripts. This resulted in enhanced secretion of proangiogenic cytokines and angiogenesis in vitro and in vivo . In SCCHN cells overexpressing GALR2, inactivation of TTP increased secretion of IL-6 and VEGF, whereas inhibition of p38 activated TTP and decreased cytokine secretion. Here, we report that GALR2 stimulates tumor angiogenesis in SCCHN via p38-mediated inhibition of TTP with resultant enhanced cytokine secretion. Given that p38 inhibitors are in clinical use for inflammatory disorders, GALR2/p38-mediated cytokine secretion may be an excellent target for new s investigated in mouse xenograft, chick chorioallantoic membrane, and the clinically relevant mouse orthotopic floor-of-mouth models. GALR2 induced angiogenesis via p38-MAPK?mediated secretion of proangiogenic cytokines, VEGF, and interleukin-6 (IL-6). Moreover, GALR2 activated small-GTP-protein, RAP1B, thereby inducing p38-mediated inactivation of tristetraprolin (TTP), which functions to destabilize cytokine transcripts. This resulted in enhanced secretion of proangiogenic cytokines and angiogenesis <i>in vitro</i> and <i>in vivo</i>. In SCCHN cells overexpressing GALR2, inactivation of TTP increased secretion of IL-6 and VEGF, whereas inhibition of p38 activated TTP and decreased cytokine secretion. Here, we report that GALR2 stimulates tumor angiogenesis in SCCHN via p38-mediated inhibition of TTP with resultant enhanced cytokine secretion. Given that p38 inhibitors are in clinical use for inflammatory disorders, GALR2/p38-mediated cytokine secretion may be an excellent target for new adjuvant therapy in SCCHN. <i>Mol Cancer Ther; 13(5); 1323?33. 2014 AACR</i>.</p>" /> s investigated in mouse xenograft, chick chorioallantoic membrane, and the clins investigated in mouse xenograft, chick chorioallantoic membrane, and the clinically s investigated in mouse xenograft, chick chorioallantoic membras investigated in mouse xenograft, chick chorioallantoic membs investigated in mouse xenograft, chick chorioas investigated in mouse xenograft, chick chorioallantoic membrane, and the clinically relevas investigated in mouse xenograft, chick chorioallantoic membrane, and the clinically relevant mouse orthotos investigated in mouse xenograft, chick chorioallantoic membrane, and the clinically relevant mouses investigated in mouse xenograft, chick chorioallantoic membrane, and the clinically relevant mouse orthotops investigated in mouse xenograft, chick chorioalls investigated in mouse xenograft, chick chorioalls investigated in mouse xenograft, chick chorioallantoic membrane, eta name="citation_doi" content="10.1158/1535-716eta name="citation_doi" content="10.1158/1535eta name="citation_doi" content="10.1158/15eta name="citation_doi" content="10.1158/1535-7163.MCT-13-0904" /eta name="citation_doi" content="10.1158/1535-7163.MCT-13-0904" /> The Medical University of South Carolina, Columbia, Sou The Medical University of South Carolina, Columbia, South Carolina" /> Craniofacial Biology, The Medical University of South CarolinaCraniofacial Biology, The Medical University of South Carolina, Columbia, South Carolina" /> Carolina" /> _journal_title=Cell;citation_journal_abbrev=Cell;citation_author=D. Hanahan;citation_author=RA. Weinberg;citation_title=Hallmarks of cancer: the next generation.;citation_pages=646-674;citation_volume=144;citation_year=2011;citation_issue=5;citation_pmid=21376230;citation_doi=10.1016/j.cell.2011.02.013" /> es=513-517;citation_volume=174;citation_year=1997;citation_issue=5;citation_pmid=9374227;citation_doi=10.1016/S0002-9610(97)00166-9" /> e=Tristetraprolin regulates interleukin-6 expression through p38 MAPK-dependent affinity changes with mRNA 3' untranslated region.;citation_pages=629-637;citation_volume=31;citation_year=2011;citation_issue=8;citation_pmid=21457063;citation_doi=10.1089/jir.2010.0154" /> ion_title=Rap1 mediates galanin receptor 2-induced proliferation and survival in squamous cell carcinoma.;citation_pages=1110-1118;citation_volume=23;citation_year=2011;citation_issue=7;citation_pmid=21345369;citation_doi=10.1016/j.cellsig.2011.02.002" /> _issue=23;citation_issn=1078-0432;citation_pmid=19047085;citation_doi=10.1158/1078-0432.CCR-07-4673" /> /j.bbrc.2012.11.124" /> itation_title=Inactivation or Loss of TTP Promotes Invasion in Head and Neck Cancer via Transcript Stabilization and Secretion of MMP9, MMP2, and IL-6;citation_volume=19;citation_year=2013;citation_pmid=23349315;citation_doi=10.1158/1078-0432.CCR-12-2927" /> itation_pmid=16436672;citation_doi=10.2353/ajpath.2006.050132" /> ear=1999;citation_issue=3;citation_pmid=10512765;citation_doi=10.1006/bbrc.1999.1454" /> citation_volume=113;citation_year=2008;citation_issue=4;citation_pmid=18536030;citation_doi=10.1002/cncr.23615" /> 44" /> ontent="citation_journal_title=Nature;citation_journal_abbrev=Nature;citation_author=JC. Lee;citation_author=JT. Laydon;citation_author=PC. McDonnell;citation_author=TF. Gallagher;citation_author=S. Kumar;citation_author=D. Green;citation_title=A protein kinase involved in the regulation of inflammatory cytokine biosynthesis.;citation_pages=739-746;citation_volume=372;citation_year=1994;citation_issue=6508;citation_issn=0028-0836;citation_pmid=7997261;citation_doi=10.1038/372739a0" /> ation_year=2011;citation_pmid=21975930;citation_doi=10.1158/0008-5472.CAN-10-3192" /> author=K. Misawa;citation_author=Y. Misawa;citation_title=Galanin and galanin receptor type 1 suppress proliferation in squamous carcinoma cells: activation of the extracellular signal regulated kinase pathway and induction of cyclin-dependent kinase inhibitors.;citation_pages=5762-5771;citation_volume=26;citation_year=2007;citation_issue=39;citation_pmid=17384686;citation_doi=10.1038/sj.onc.1210384" /> 16/j.regpep.2003.10.022" /> 11111616/j.regpep.2003.10.022" /> jjojournals.org/sites/default/files/advagg_css/css__vP96nkAt3EeLU62QRdHXKZuS9tqQ1EMDJC_PSKd7hEk___ZRIWZBmdtp7-lbo1EncXvDMhoO2mKRnKh3xIt6ztiY__wCgJivhjKDUA_L30nXcLymyObV-qgh2h7ylCdP9o-UQ.css" media="all" /> ag.cmdaaa eaaaaa aa al","al","order":["narrow","normal","wide"],"queries":{"narrow":"all and (min-width: 768px) and (min-device-widal","orderal","order":["narrow","normal","wide"],"queries":{"narrow":"all and (min-width: 768px) and (min-device-width: 768px), (max-device-width: 800px) and (min-width: 768px) and (orientation:landscape)","normal":"all and (min-width: 980px) and (min-deviceal","order":["narrow","normal","order":["narrowal","ordeal","order"al","order":["narrow","normal","wide"],"queries":{"narrow":"al","order":["narrow","normal","wide"],"queries":{"narral","oral","orderal","order":["narrow","normal","wide"],"queries":{"narrow":"all and (min-width: 768px) and (min-device-width: 768al","order":["narrow","normal","wide"],"queries":{"narrow":"alal","order":["narrow","normal","wide"],"queries":{"narrow":"all and (min-width: 768px) and (min-device-widthal","order":["narrow","normal","wide"],"queries":{"narrow":"all and (min-width: 768px) and (min-device-width: 768px), (max-devial","order":["narrow","normal","wide"],"queries":{"narrow":"all and (min-width: 768px) and (mal","order":["narrow","normal","wide"],"queries":{"narral","order":["narrow","normal","wide"],"queries":{"narrow":"all and (min-width: 768px) and (min-device-width: 768pal","order":["narrow","normal","wide"],"queries":{"narroal","order":["narrow","normal","wide"],"queries":{"narroal","order":["narrow","noal","order":["narrow","normal","wide"],"queries":{"narrow":"all and (min-width: 768px) andal","order":["narrow","normal","wide"],"queries":{"narrow":"all and (min-width: 768px) and ="http://www.="ht="http://www.aac="http://www.aacrjournals.org/" data-hide-link-title="0" class="" data-icon-position="">A="http://www.aac="ht="http="http://www.aacrjournals.org/" data-hide-link-title="0" class="" data-icon="http://www.aacrjournals.org/" data-hide-link-t="ht="http="http://www.aacrjournals.org/" data-hide-link-title="0" class="" data-icon-position=""="http://www.aacrjournals.="ht="http="http://www.aacrjournals.org/" data-hide-link-title="0" class="" data-icon-position="">AACR Jou="http://www.aacrjournals.="ht="http="http://www.aacrjournals.org/" data-hide-link-title="0" class="" data-icon-posi="http://www.aa="ht="http="http://www.aacrjournals.org/" data-hide-link-title="0" class="" data-icon-position=="http://www.aacrjournal="ht="http="http://www.aacrjournals.org/" data-hide-link-title="0" class="" data-ico="http://www.aacrjournals="ht="http="http://www.aacrjournals.org/" data-hide-link-title="0" class="" data-icon-pos="http://www.aacrjournals.org="ht="http="htt="http="htt="http:/
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  • Figure 3.

    GALR2 induces p38-mediated inhibition of TTP to enhance angiogenesis. A, schematic representation of signaling pathway showing GALR2-mediated phosphorylation and activation of p38 that inhibits TTP via phosphorylation. Inactivation or genetic loss (by siRNA) of TTP prevents cytokine degradation giving rise to overall steady state increase in cytokines and acts as angiogenic switch to tumor growth. Chemical inhibitor (SB203580) to p38 kinase activity can dephosphorylate TTP to its active form and degrade cytokines. Alternatively targeting individual cytokines by siRNA could be used to control this angiogenic signal. Upstream inhibitors to angiogenesis might be a better treatment option (left). UM-SCC-1-GALR2 cells were serum starved for 4 hours and then treated with 10 ?mol/L of SB203580 for 2 hours and were then stimulated with 10 nmol/L galanin for 10 minutes or vehicle control. Clarified cell lysates were immunoprecipitated with TTP antibody, and blotted with anti-TTP and anti-phosphoserine antibodies (right). B, UM-SCC-1-GALR2 cells were transfected with siTTP or NT-siRNA and were treated with 10 ?mol/L of SB203580 or vehicle control. Cell lysates were immunoblotted with VEGF, IL-6, TTP, and actin antibodies (left). Conditioned medium was collected from each of the treatment groups and ELISA was performed for VEGFf="/highwiref="/highwire/powerpoint/44430" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint

    frfrom 10 representative fields (*, P < 0.02). D, IL-6 was transiently downregufrom 10from 10 representative fields (*, P < 0.02). D, IL-6 was transiently downregulated in UM-SCC-1-GALR2 cells with si-IL-6 and immunoblotted (left) and similarly in vitro tubule formation assay was performed with condifrom 10from 10 representative fields (*, P < 0.02). D, IL-6 was transiently downregulated in UM-SCC-1-GALR2 cells with si-IL-6 and immfrom 10from 10 representative fields (*, P < 0.02). D, IL-6 was transiently downregulated in UM-SCC-1-GALR2 cells with si-IL-6 and immunoblotted (left) and similarly in vitro tubule formation assay was performed with conditioned medium collected from cells (middle left) and quantified (right; *, P < 0.02). Data are representative of three identfrom 10from 10 representative fields (*, P from 10from 10 representative fields (*, P < 0.02). D, IL-6 was transiently dowfrfrom 10 representative fields (*, from 10, left).,, left).

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    Given that GALR2 promotes angiogenesis (Fig. 1) and induces secretion of multiple cytokines, (Fig. 4B, middle-left panel and right graphs). The impact of TTP suss="xref-fiss="xref-fig" href="#F4">Fig. 4B, middle-left panel and right graphs). The impact of TTP suppression on tumor angiogenesis in vivo was investigated on the CAM. A significant incrss="xress="xref-fig" href="#F4">Fig. 4B, middle-left panel and right graphs). The impact of TTP suppression on tumorss="xress="xref-fig" href="#F4">Fig. 4B, middless="xss="xref-fig" href="#F4">Fig. 4B, miss="xref-fig" href="#F4">Fig.ss="xref-fig" href="#F4">Fig. 4Bss="xref-fig" href="#F4">Figs="highwire-fragment fragment-imFigure 4.s="highwirFigure 4..medium.gif.medium.med.mediu.mediu.medium.gif" width="440" height="386"/>.medium.gif" wi.med.medi.medium.gif" width=".medium.gif" wi.med.medi.medium.gif" width="440" heigh.medium.gif" width=.med.medi.medi.mediu.medium.gif" width="440" .medium.gif" width="440" height=".medium.g.medium.gif" width="440" height="386"/>