Involvement of the TGFbeta pathway in the regulation of alpha5 beta1 integrins by caveolin-1 in human glioblastoma.
Fiche publication
Date publication
août 2012
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHASTAGNER Pascal, Dr DONTENWILL Monique, Pr ENTZ-WERLE Natacha, Dr GUENOT Dominique, Dr GUERIN Eric, Dr MARTIN Sophie, Dr PINEL Sophie
Tous les auteurs :
Cosset EC, Godet J, Entz-Werle N, Guerin E, Guenot D, Froelich S, Bonnet D, Pinel S, Plenat F, Chastagner P, Dontenwill M, Martin S
Lien Pubmed
Résumé
Caveolin-1 plays a crucial role in the development of cancer and its progression. We previously reported that glioblastoma cells expressing low levels of caveolin-1 exerted a more aggressive phenotype than cells expressing high levels. Such phenotype was due to the induction of alpha(5) beta(1) integrin subsequent to the depletion of caveolin-1. Caveolin-1 was identified as a transcriptional repressor of alpha(5) beta(1) integrin. The current study was designed to identify in vitro, the molecular mechanisms by which caveolin-1 controls alpha(5) beta(1) integrin expression and to determine if a negative correlation between caveolin-1 and alpha(5) beta(1) integrins also exists in biopsies and xenografted human brain tumors. We showed that depletion of caveolin-1 lead to the activation of the TGFbeta/TGFbetaRI/Smad2 pathway which in turn induced the expression of alpha(5) beta(1) integrins. We showed that cells expressing the lowest levels of caveolin-1 but the highest levels of alpha(5) beta(1) integrins and TGFbetaRI were the most sensitive to a alpha(5) beta(1) integrin antagonist and a TGFbetaRI inhibitor. Screening human glioma biopsies and human glioblastoma xenografts, we isolated subgroups with either low levels of caveolin-1 but high levels of alpha(5) beta(1) integrin and TGFbetaRI or high levels of caveolin-1 but low levels of alpha(5) beta(1) integrin and TGFbetaRI. In conclusion, caveolin-1 controls alpha(5) beta(1) integrin expression through the TGFbeta/TGFbetaRI/Smad2 pathway. The status of caveolin-1/alpha(5) beta(1) integrins/TGFbetaRI might be a useful marker of the tumor evolution/prognosis as well as a predictor of anti-TGFbeta or anti-alpha(5) beta(1) integrin therapies.
Référence
Int J Cancer. 2012 Aug 1;131(3):601-11