title: Connexin43highprostate cancer cells induce endothelial connexin43 up-regulation through the activation of intercellular ERK1/2-dependent signaling axis.
abstract: Connexin(Cx)43 regulates the invasive potential of prostate cancer cells and participates in their extravasation. To address the role of endothelial Cx43 in this process, we analyzed Cx43 regulation in human umbilical vein endothelial cells in the proximity of Cx43high(DU-145 and MAT-LyLu) and Cx43lowprostate cancer cells (PC-3 and AT-2). Endothelial Cx43 up-regulation was observed during the diapedesis of DU-145 and MAT-LyLu cells. This process was attenuated by transient Cx43 silencing in cancer cells and by chemical inhibition of ERK1/2-dependent signaling in endothelial cells. Cx43 expression in endothelial cells was insensitive to the inhibition of gap junctional intercellular coupling between Cx43highprostate cancer and endothelial cells by 18α-glycyrrhetinic acid. Instead, endothelial Cx43 up-regulation was correlated with the local contraction of endothelial cells and with their activation in the proximity of Cx43highDU-145 and MAT-LyLu cells. It was also sensitive to pro-inflammatory factors secreted by peripheral blood monocytes, such as TNFα. In contrast to Cx43lowAT-2 cells, Cx43lowPC-3 cells produced angioactive factors that locally activated the endothelial cells in the absence of endothelial Cx43 up-regulation. Collectively, these data show that Cx43lowand Cx43highprostate cancer cells can adapt discrete, Cx43-independent and Cx43-dependent strategies of diapedesis. Our observations identify a novel strategy of prostate cancer cell diapedesis, which depends on the activation of intercellular Cx43/ERK1/2/Cx43 signaling axis at the interfaces between Cx43highprostate cancer and endothelial cells.
authors.affiliation: Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Piwowarczyk
authors.affiliation: Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
authors.forename: Milena
authors.initials: M
authors.lastname: Paw
authors.affiliation: Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
authors.forename: Damian
authors.initials: D
authors.lastname: Ryszawy
authors.affiliation: Department of Clinical Immunology, Institute of Paediatrics, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Rutkowska-Zapała
authors.affiliation: Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Madeja
authors.affiliation: Department of Clinical Immunology, Institute of Paediatrics, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Siedlar
authors.affiliation: Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland. Electronic address: jarek.czyz@uj.edu.pl.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Czyż
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D018031:Connexin 43 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005419:Flavonoids / Q000494:pharmacology; D017629:Gap Junctions / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006034:Glycyrrhetinic Acid / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D018031:Connexin 43; D017077:Culture Media, Conditioned; D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D006034:Glycyrrhetinic Acid; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Cx43; Diapedesis; ERK1/2; Endothelial cells; Prostate cancer