Tumor promoting effects of CD95 signaling in chemoresistant cells

We show that CD95 triggering results in an increased metastatic ability in resistant cells. Moreover, oxaliplatin treatment itself stimulates cell migration and decreases cell adhesion through CD95 activation, since CD95 expression inhibition by siRNA blocks the promigratory effects of oxaliplatin. These promigratory effects are related to the epithelia-to-mesenchymal transition (EMT) phenomenon, as evidenced by the up-regulation of some transcription factors and mesenchymal markers both in vitro and in vivo.We conclude that oxaliplatin treatment in cells that have acquired resistance to oxaliplatin-induced apoptosis results in tumor-promoting effects through the activation of CD95 signaling and by inducing EMT, all these events jointly contributing to a metastatic phenotype.CD95 (APO-1/Fas), a 48 kDa membrane protein belonging to the TNF receptor superfamily, activates caspase-dependent apoptosis in susceptible cells when is activated by its natural ligand (CD95L). There are two different cell types that use distinct CD95 apoptosis signaling pathways. After CD95 triggering, type I cells activate caspase-8 at the death-inducing signaling complex (DISC) followed by activation of caspase-3. Apoptosis induction in these cells is not sensitive to mitochondria pathway inhibition. However, in type II cells DISC formation is strongly reduced and the activation of caspase-8 and caspase-3 is produced downstream of mitochondrial events. Thus, inhibition of the mitochondrial role in these cells by overexpression of Bcl-2 or Bcl-xL blocks apoptosis [1,2]. This classification is related to cell phenotype, since type I cells correspond to mesenchymal tumors and type II cells display a more epithelial phenotype [3].Many cancer cells acquire survival advantage during tumor progression by decreasing its sensitivity to CD95-induced apoptosis [4,5]. Some mechanisms affecting CD95 sensitivity include downregulation of CD95 protein expression [6], blocking of the active receptor site by