Despite the complexity of the transformation process, several model systems have been developed in which normal cells are transformed in a step-wise manner by introduction of genetic elements (telomerase, SV40ER viral genes and oncogenes). In this system, only the transformed cells go into TRAIL-induced apoptosis. As senescent-secreted factors have already been involved in promoting some of the tumor characteristics (proliferation, invasion and others), our objective was to assess its potential effect on the acquisition of sensitivity to TRAIL. When all the cells of the transformation system were incubated with conditioned medium of senescent cells (CMS) the sensitization to TRAIL was observed only in the pre-transformed, but never in normal or immortalized cells. Thus, we concluded that the different steps of transformation provide a cellular and molecular context that acts in synergy with the CMS to promote TRAIL sensitivity. These observations emphasize the specific role of senescent cells and their secretory phenotype. We then studied the mechanisms activated inthe pre-transformed cells by the CMS, responsible for their sensitization to TRAIL. Our results suggest a key role of the Myc-FLIPL axis in signaling activated by the CMS.
