title: Senescence-secreted factors activate Myc and sensitize pretransformed cells to TRAIL-induced apoptosis.
abstract: Senescent cells secrete a plethora of factors with potent paracrine signaling capacity. Strikingly, senescence, which acts as defense against cell transformation, exerts pro-tumorigenic activities through its secretome by promoting tumor-specific features, such as cellular proliferation, epithelial-mesenchymal transition and invasiveness. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the unique activity of activating cell death exclusively in tumor cells. Given that the senescence-associated secretome (SAS) supports cell transformation, we asked whether SAS factor(s) would establish a program required for the acquisition of TRAIL sensitivity. We found that conditioned media from several types of senescent cells (CMS) efficiently sensitized pretransformed cells to TRAIL, while the same was not observed with normal or immortalized cells. Dynamic transcription profiling of CMS-exposed pretransformed cells indicated a paracrine autoregulatory loop of SAS factors and a dominant role of CMS-induced MYC. Sensitization to TRAIL coincided with and depended on MYC upregulation and massive changes in gene regulation. Senescent cell-induced MYC silenced its target gene CFLAR, encoding the apoptosis inhibitor FLIPL , thus leading to the acquisition of TRAIL sensitivity. Altogether, our results reveal that senescent cell-secreted factors exert a TRAIL-sensitizing effect on pretransformed cells by modulating the expression of MYC and CFLAR. Notably, CMS dose-dependent sensitization to TRAIL was observed with TRAIL-insensitive cancer cells and confirmed in co-culture experiments. Dissection and characterization of TRAIL-sensitizing CMS factors and the associated signaling pathway(s) will not only provide a mechanistic insight into the acquisition of TRAIL sensitivity but may lead to novel concepts for apoptogenic therapies of premalignant and TRAIL-resistant tumors.
authors.affiliation: Department Functional Genomics and Cancer, Equipe Labellisée Ligue Contre le Cancer, Institut Génétique de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/UdS/CERBM, BP 10142, 67404, Illkirch-Cedex, C.U. de Strasbourg, France.
authors.forename: Jelena
authors.initials: J
authors.lastname: Vjetrovic
authors.forename: Pattabhiraman
authors.initials: P
authors.lastname: Shankaranarayanan
authors.forename: Marco A
authors.initials: MA
authors.lastname: Mendoza-Parra
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology; D017077:Culture Media, Conditioned; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D017077:Culture Media, Conditioned; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human
keywords: Myc; TRAIL; apoptosis; secretome; senescence; tumor