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Title: Senescence secreted factors activate Myc and sensitize pre-transformed cells to TRAIL-induced apoptosis      
keywords:
Transcriptome or Gene expression
ID:
PRJNA215419
description:
Senescent cells secrete a plethora of factors with potent paracrine signaling capacity. Strikingly, senescence, which acts as a defense against cell transformation, exerts pro-tumorigenic activities through its secretome by promoting numerous 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 supports cell transformation, we asked whether factor(s) of this secretome 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 pre-transformed cells to TRAIL, while the same was not observed with normal or immortalized cells. Dynamic transcription profiling analysis of CMS-exposed pre-transformed cells revealed paracrine autoregulatory loop of senescence-associated secretome factors and a dominant role of CMS-induced MYC. Sensitization to TRAIL coincided with MYC upregulation and massive changes in gene regulation. CMS-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 pre-transformed 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) may provide a mechanistic insight in the acquisition of TRAIL sensitivity and lead to novel concepts for the apoptogenic therapy of pre-malignant and TRAIL-resistant tumors. Overall design: Pre-transformed BJEL cells were incubated with CMS for 0, 1, 3, 6, 8, 16 or 24 h respectively. Total RNA has been extracted from each time point and used for gene expression analysis (Affymetrix Human Gene 1.0 ST Arrays).
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landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA215419
authentication:
none
authorization:
none
ID:
pmid:24589226
name:
Homo sapiens
ncbiID:
ncbitax:9606
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject