title: Down-regulation of Connexin43 expression reveals the involvement of caveolin-1 containing lipid rafts in human U251 glioblastoma cell invasion.
abstract: Glioblastoma cells are characterized by high proliferation and invasive capacities. Tumor development has been associated with a decrease of gap-junctional intercellular communication, but the concrete involvement of gap junction proteins, connexins, remains elusive since they are also suspected to promote cell invasion. In order to better understand how connexins control the glioma cell phenotype, we studied the consequences of inhibiting the intrinsic expression of the major astrocytic connexin, Connexin43, in human U251 glioblastoma cells by the shRNA strategy. The induced down-regulation of Cx43 expression has various effects on the U251 cells such as increased clonogenicity, angiogenesis and decreased adhesion on specific extracellular matrix proteins. We demonstrate that the invasion capacity measured in vitro and ex vivo correlates with Cx43 expression level. For the first time in a cancer cell context, our work demonstrates that Cx43 cofractionates, colocalizes and coimmunoprecipitates with a lipid raft marker, caveolin-1 and that this interaction is inversely correlated to the level of Cx43. This localization of Cx43 in these lipid raft microdomains regulates both homo- and heterocellular gap junctional communications (respectively between U251 cells, or between U251 cells and astrocytes). Moreover, the adhesive and invasive capacities are not dependent, in our model, on Cav-1 expression level. Our results tend to show that heterocellular gap junctional communication between cancer and stroma cells may affect the behavior of the tumor cells. Altogether, our data demonstrate that Cx43 controls the tumor phenotype of glioblastoma U251 cells and in particular, invasion capacity, through its localization in lipid rafts containing Cav-1.
authors: Institute of Cellular Physiology and Biology, University of Poitiers, CNRS UMR 6187, Poitiers, France.
authors: Pierre-Olivier
authors: PO
authors: Strale
authors: Jonathan
authors: J
authors: Clarhaut
authors: Coralie
authors: C
authors: Lamiche
authors: Laurent
authors: L
authors: Cronier
authors: Marc
authors: M
authors: Mesnil
authors: Norah
authors: N
authors: Defamie
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000032:analysis / Q000378:metabolism*; D002448:Cell Adhesion; D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002645:Chickens; D018031:Connexin 43 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology
chemical_list: D051242:Caveolin 1; D018031:Connexin 43