Alphavbeta3/alphavbeta5 integrins-FAK-RhoB: a novel pathway for hypoxia regulation in glioblastoma.
The presence of hypoxic areas in glioblastoma is an important determinant in tumor response to therapy and, in particular, to radiotherapy. Here we have explored the involvement of integrins, up to now known as regulators of angiogenesis and invasion, in the regulation of tumor hypoxia driven from the tumor cell. We first show that hypoxia induces the recruitment of alpha(v)beta(3) and alpha(v)beta(5) integrins to the cellular membrane of U87 and SF763 glioblastoma cells, thereby activating the focal adhesion kinase (FAK). We then show that inhibiting alpha(v)beta(3) or alpha(v)beta(5) integrins in hypoxic cells with a specific inhibitor or with siRNA decreases the hypoxia-inducible factor 1alpha (HIF-1alpha) intracellular level. This integrin-dependent regulation of HIF-1alpha is mediated through the regulation of FAK, which in turn activates the small GTPase RhoB, leading to the inhibition of GSK3-beta. Furthermore, silencing this pathway in glioma cells of established xenografts dramatically reduces glioma hypoxia, associated with a significant decrease in vessel density. Our present results unravel a new mechanism of hypoxia regulation by establishing the existence of an alpha(v)beta(3)/alpha(v)beta(5) integrin-dependent loop of hypoxia autoregulation in glioma. Targeting this hypoxia loop may be crucial to optimizing radiotherapy efficiency.
Institut National de la Santé et de la Recherche Médicale (INSERM) U563, Department of Signaling, Oncogenesis, and Therapeutic Innovation, Toulouse, France.
Nicolas
N
Skuli
Sylvie
S
Monferran
Caroline
C
Delmas
Gilles
G
Favre
Jacques
J
Bonnet
Christine
C
Toulas
Elizabeth
E
Cohen-Jonathan Moyal
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D010100:Oxygen / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014183:Transplantation, Heterologous; D020743:rhoB GTP-Binding Protein / Q000378:metabolism*; D000099200:Scaffold Protein ILK
D051416:Focal Adhesion Protein-Tyrosine Kinases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039302:Integrin alphaVbeta3; D010100:Oxygen; D017346:Protein Serine-Threonine Kinases; D019030:Receptors, Vitronectin; D020743:rhoB GTP-Binding Protein; D000099200:Scaffold Protein ILK; C497442:HIF1A protein, human; C064660:integrin alphaVbeta5