Caveolin-1 regulates glioblastoma aggressiveness through the control of α5β1 integrin expression and modulates glioblastoma responsiveness to SJ749, an α5β1 integrin antagonist

Abstract

Caveolin-1 plays a checkpoint function in the regulation of processes often altered in cancer. Although increased expression of caveolin-1 seems to be the norm in the glioma family of malignancies, populations of caveolin-1 positive and negative cells coexist among glioblastoma specimens. As no data are available to date on the contribution of such cells to the phenotype of glioblastoma, we manipulated caveolin-1 in the glioblastoma cell line U87MG. We showed that caveolin-1 plays a critical role in the aggressiveness of glioblastoma. We identified integrins as the main set of genes affected by caveolin-1. We reported here that the phenotypic changes observed after caveolin-1 modulation were mediated by alpha(5)beta(1) integrins. As a consequence of the regulation of alpha(5)beta(1) levels by caveolin-1, the sensitivity of cells to the specific alpha(5)beta(1) integrin antagonist, SJ749, was affected. Mediator of caveolin-1 effects, alpha(5)beta(1) integrin, is also a marker for glioma aggressiveness and an efficient target for the treatment of glioma especially the ones exerting the highest aggressive phenotype.

Pathologic Caveolin-1 Regulation of PTEN in Idiopathic Pulmonary Fibrosis

“…1 Prior studies suggest that caveolin-1 may associate with integrin and regulate integrin signaling. [25][26][27][28] Since we have found that during control fibroblast interaction with collagen, PTEN associates with caveolin-1 and suppresses activation of Akt, we were interested in determining whether ␤1 integrin also associates with caveolin-1 in a protein complex. We found that an endogenous protein complex consisting of caveolin-1, ␤1 integrin, and PTEN could be coprecipitated from normal fibroblasts ( Figure 5, A and B).…”

Integrin α5β1 Plays a Critical Role in Resistance to Temozolomide by Interfering with the p53 Pathway in High-Grade Glioma

“…Through the use of non-peptidic a5b1 integrin antagonists and GBM cell lines, we previously showed that a5b1 integrin may be a therapeutic target for these tumors (8,9) and that concomitant addition of a5b1 antagonists sensitizes p53 wild-type (p53-wt) glioma cells to chemotherapeutic drugs (10). The presence of p53 mutations in high-grade glioma varied across GBM subtypes with 0%, 21%, 32%, and 54% in classical, neural, mesenchymal, and proneural subtypes, respectively (11).…”

Caveolin-1-negative head and neck squamous cell carcinoma primary tumors display increased epithelial to mesenchymal transition and prometastatic properties

“…In accordance, blocking α 5 β 1 integrin activity using specific antagonist such as K34c and compound 1, used to successfully block this integrin in other model of solid tumors [10-12, 26, 43], strongly impaired single cell migration, evasion and invasion suggesting that α 5 β 1 integrin is the main integrin involved in the motility and invasiveness of shRNA cav-1 -cells. As shown in glioblastoma, depletion of Cav1 in HNSCC enhanced α 5 β 1 integrin expression endowing cells with an aggressive phenotype [10,11]. It is obvious that beside FN, collagen also efficiently promotes evasion out of the tumor mass.…”

“…Subclassification of patients according to α 5 β 1 integrins/ Cav1 levels showed the existence of a cluster of patients exerting low Cav1/high α 5 β 1 integrins levels [11] which was correlated with reduced overall survival [12]. Cav1 is the principal structural protein of caveolae able to control the subcellular distribution, activity and expression of molecules and receptors [13,14].…”