title: Involvement of the TGFβ pathway in the regulation of α5 β1 integrins by caveolin-1 in human glioblastoma.
abstract: 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 α(5) β(1)  integrin subsequent to the depletion of caveolin-1. Caveolin-1 was identified as a transcriptional repressor of α(5) β(1)  integrin. The current study was designed to identify in vitro, the molecular mechanisms by which caveolin-1 controls α(5) β(1)  integrin expression and to determine if a negative correlation between caveolin-1 and α(5) β(1)  integrins also exists in biopsies and xenografted human brain tumors. We showed that depletion of caveolin-1 lead to the activation of the TGFβ/TGFβRI/Smad2 pathway which in turn induced the expression of α(5) β(1)  integrins. We showed that cells expressing the lowest levels of caveolin-1 but the highest levels of α(5) β(1)  integrins and TGFβRI were the most sensitive to a α(5) β(1)  integrin antagonist and a TGFβRI inhibitor. Screening human glioma biopsies and human glioblastoma xenografts, we isolated subgroups with either low levels of caveolin-1 but high levels of α(5) β(1)  integrin and TGFβRI or high levels of caveolin-1 but low levels of α(5) β(1)  integrin and TGFβRI. In conclusion, caveolin-1 controls α(5) β(1)  integrin expression through the TGFβ/TGFβRI/Smad2 pathway. The status of caveolin-1/α(5) β(1)  integrins/TGFβRI might be a useful marker of the tumor evolution/prognosis as well as a predictor of anti-TGFβ or anti-α(5) β(1)  integrin therapies.
authors: Université de Strasbourg, LBP, CNRS UMR 7213, Illkirch, France.
authors: Erika C
authors: EC
authors: Cosset
authors: Julien
authors: J
authors: Godet
authors: Natacha
authors: N
authors: Entz-Werlé
authors: Eric
authors: E
authors: Guérin
authors: Dominique
authors: D
authors: Guenot
authors: Sébastien
authors: S
authors: Froelich
authors: Dominique
authors: D
authors: Bonnet
authors: Sophie
authors: S
authors: Pinel
authors: François
authors: F
authors: Plenat
authors: Pascal
authors: P
authors: Chastagner
authors: Monique
authors: M
authors: Dontenwill
authors: Sophie
authors: S
authors: Martin
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051242:Caveolin 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D034622:RNA Interference; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D014408:Biomarkers, Tumor; C495540:CAV1 protein, human; D051242:Caveolin 1; D039081:Integrin alpha5beta1; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta