title: Oncogenic extracellular HSP70 disrupts the gap-junctional coupling between capillary cells.
abstract: High levels of circulating heat shock protein 70 (HSP70) are detected in many cancers. In order to explore the effects of extracellular HSP70 on human microvascular endothelial cells (HMEC), we initially used gap-FRAP technique. Extracellular human HSP70 (rhHSP70), but not rhHSP27, blocks the gap-junction intercellular communication (GJIC) between HMEC, disrupts the structural integrity of HMEC junction plaques, and decreases connexin43 (Cx43) expression, which correlates with the phosphorylation of Cx43 serine residues. Further exploration of these effects identified a rapid transactivation of the Epidermal Growth Factor Receptor in a Toll-Like Receptor 4-dependent manner, preceding its internalization. In turn, cytosolic Ca2+ oscillations are generated. Both GJIC blockade and Ca2+ mobilization partially depend on ATP release through Cx43 and pannexin (Panx-1) channels, as demonstrated by blocking activity or expression of channels, and inactivating extracellular ATP. By monitoring dye-spreading into adjacent cells, we show that HSP70 released from human monocytes in response to macrophage colony-stimulating factor, prevents the formation of GJIC between monocytes and HMEC. Therapeutic manipulation of this pathway could be of interest in inflammatory and tumor growth.
authors: INSERM, U866, Faculty of Medecine, Dijon, France.
authors: Dominique
authors: D
authors: Thuringer
authors: INSERM, U866, Faculty of Medecine, Dijon, France.
authors: Kevin
authors: K
authors: Berthenet
authors: CNRS ERL7368, STIM Lab, University of Poitiers, Poitiers, France.
authors: Laurent
authors: L
authors: Cronier
authors: INSERM, U866, Faculty of Medecine, Dijon, France.|University of Burgundy, Dijon, France.
authors: Gaetan
authors: G
authors: Jego
authors: INSERM, U1009, Institut Gustave Roussy, Villejuif, France.
authors: Eric
authors: E
authors: Solary
authors: INSERM, U866, Faculty of Medecine, Dijon, France.|University of Burgundy, Dijon, France.|CGFL, BP77980 21000 Dijon, France.
authors: Carmen
authors: C
authors: Garrido
mesh_terms: D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D018031:Connexin 43 / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D018031:Connexin 43; C500216:GJA1 protein, human; D018840:HSP70 Heat-Shock Proteins; D011994:Recombinant Proteins
keywords: ATP release; Ca2+ oscillations; Cx43; HSP; pannexin