Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2021; 12:1564-1565.

Oncogenic extracellular HSP70 disrupts the gap-junctional coupling between capillary cells

Dominique Thuringer _, Kevin Berthenet, Laurent Cronier, Gaetan Jego, Eric Solary and Carmen Garrido

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Oncotarget. 2015; 6:10267-10283. https://doi.org/10.18632/oncotarget.3522

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Abstract

Dominique Thuringer1, Kevin Berthenet1, Laurent Cronier2, Gaetan Jego1,3, Eric Solary4, Carmen Garrido1,3,5

1 INSERM, U866, Faculty of Medecine, Dijon, France

2 CNRS ERL7368, STIM Lab, University of Poitiers, Poitiers, France

3 University of Burgundy, Dijon, France

4 INSERM, U1009, Institut Gustave Roussy, Villejuif, France

5 CGFL, BP77980 21000 Dijon, France

Correspondence to:

Dominique Thuringer, email:

Keywords: HSP, Cx43, pannexin, Ca2+ oscillations, ATP release

Received: January 30, 2015 Accepted: February 17, 2015 Published: March 10, 2015

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.


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