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International audience; Among the genetic and metabolic alterations that cancer cells undergo, several allow their survival under extreme environmental conditions. The resulting aberrant metabolism is compatible with tumor progression at the expenses of high energy needs, especially for maintaining high division rate. When treated with chemotherapeutic drugs many cancer cells take advantage of their ability to develop a resistance phenotype, as part of an adaptative mechanism. Two main actors of this multidrug phenotype (MDR) are represented by the P-glycoprotein and by the more recently discovered multidrug-resistance associated protein (MRP), two membrane proteins of the ABC superfamily of transporters that can extrude chemotherapeutic drugs under an ATP-dependent mechanism. We will briefly review the major metabolic aberrations that several cancers develop, followed by the molecular, genetic, structural, and functional aspects related mainly to P-glycoprotein, with a concern for the regulation of mdr gene expression. We will point out the role that membrane cholesterol may play in the MDR phenotype, relate this phenotype to bioenergetic considerations, and review the ways of modulating it by the use of new therapeutic approaches.Among the genetic and metabolic alterations that cancer cells undergo, several allow their survival under extreme environmental conditions. The resulting aberrant metabolism is compatible with tumor progression at the expenses of high energy needs, especially for maintaining high division rate. When treated with chemotherapeutic drugs many cancer cells take advantage of their ability to develop a resistance phenotype, as part of an adaptative mechanism. Two main actors of this multidrug phenotype (MDR) are represented by the P-glycoprotein and by the more recently discovered multidrug-resistance associated protein (MRP), two membrane proteins of the ABC superfamily of transporters that can extrude chemotherapeutic drugs under an ATP-dependent mechanism. We will briefly review the major metabolic aberrations that several cancers develop, followed by the molecular, genetic, structural, and functional aspects related mainly to P-glycoprotein, with a concern for the regulation of mdr gene expression. We will point out the role that membrane cholesterol may play in the MDR phenotype, relate this phenotype to bioenergetic considerations, and review the ways of modulating it by the use of new therapeutic approaches.

International audience; Several recent studies have shown that proteins of the cadherin-catenin complex are not only involved in cell-cell adhesion but also in the proliferation and differentiation processes. For the first time, we investigated the effect of the quantity of cytoplasmic beta-catenin on dermal fibroblast proliferation by overexpressing human beta-catenin in human dermal fibroblasts. Our results show that dermal fibroblasts overexpressing normal beta-catenin or a stabilized beta-catenin mutant have a higher growth rate than control fibroblasts. Moreover, when confluence is reached, the number of fibroblasts is increased when the cells overexpress beta-catenin suggesting a role for beta-catenin in the regulation of contact growth arrest. Finally, by comparing proliferation in normal dermal fibroblasts and dermal fibroblasts expressing E-cadherin we observed a negative regulatory effect of E-cadherin expression on fibroblast proliferation. These data demonstrate the involvement of beta-catenin and cadherin in the dermal fibroblast proliferation process and in contact growth arrest.Several recent studies have shown that proteins of the cadherin-catenin complex are not only involved in cell-cell adhesion but also in the proliferation and differentiation processes. For the first time, we investigated the effect of the quantity of cytoplasmic beta-catenin on dermal fibroblast proliferation by overexpressing human beta-catenin in human dermal fibroblasts. Our results show that dermal fibroblasts overexpressing normal beta-catenin or a stabilized beta-catenin mutant have a higher growth rate than control fibroblasts. Moreover, when confluence is reached, the number of fibroblasts is increased when the cells overexpress beta-catenin suggesting a role for beta-catenin in the regulation of contact growth arrest. Finally, by comparing proliferation in normal dermal fibroblasts and dermal fibroblasts expressing E-cadherin we observed a negative regulatory effect of E-cadherin expression on fibroblast proliferation. These data demonstrate the involvement of beta-catenin and cadherin in the dermal fibroblast proliferation process and in contact growth arrest.

International audience; xxx