CFLAR
CASP8 and FADD-like apoptosis regulator precursor (Caspase homolog) (CASH) (Caspase-eight-related protein) (Casper) (Caspase-like apoptosis regulatory protein) (CLARP) (Cellular FLICE-like inhibitory protein) (c-FLIP) (FADD-like antiapoptotic molecule 1) (FLAME-1) (Inhibitor of FLICE) (I-FLICE) (MACH-related inducer of toxicity) (MRIT) (Usurpin) [Contains: CASP8 and FADD-like apoptosis regulator subunit p43; CASP8 and FADD-like apoptosis regulator subunit p12] [CASH] [CASP8AP1] [CLARP] [MRIT]
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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.
MeSH Terms
- Amino Acid Sequence
- Apoptosis
- CASP8 and FADD-Like Apoptosis Regulating Protein
- Cell Line
- Cell Transformation, Neoplastic
- Cellular Senescence
- Culture Media, Conditioned
- Fibroblasts
- Gene Expression Regulation
- Humans
- Molecular Sequence Data
- Proto-Oncogene Proteins c-myc
- TNF-Related Apoptosis-Inducing Ligand
Keywords
- Myc
- TRAIL
- apoptosis
- secretome
- senescence
- tumor
Fully competent oocytes represent the final outcome of a highly selective process. The decline of oocyte competence with ageing, coupled to quantitative decrease of ovarian follicles has been well established; on the contrary, its molecular bases are still poorly understood. Through quantitative high throughput PCR, we investigated the role of apoptotic machinery (AM) in this process. To this aim, we determined AM transcriptome in mature MII oocyte pools from women aged more than 38 years (cohort A), and compared to women aged up to 35 years (cohort B). Subsequently, 10 representative AM genes were selected and analyzed in 33 single oocytes (15 from cohort A and 18 from cohort B). These investigations led us to identify: (1) the significant upregulation of proapoptotic genes such us CD40, TNFRSF10A, TNFRSF21 and the downregulation of antiapoptotic genes such as BCL2 and CFLAR in cohort A respect to cohort B; (2) AM transcripts that have not previously been reported in human oocytes (BAG3, CD40, CFLAR, TNFRSF21, TRAF2, TRAF3). Our results demonstrated that during maturation the oocytes from older women selectively accumulate mRNAs that are able to trigger the extrinsic apoptotic pathway. These data contribute to clarify the molecular mechanisms of AM involvement in the natural selection strategy of removing low quality oocytes and preventing unfit or poorly fit embryos.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Adult
- Aging
- Apoptosis
- Apoptosis Regulatory Proteins
- CASP8 and FADD-Like Apoptosis Regulating Protein
- CD40 Antigens
- Down-Regulation
- Female
- Humans
- Maternal Age
- Oocytes
- Proto-Oncogene Proteins c-bcl-2
- Receptors, TNF-Related Apoptosis-Inducing Ligand
- Receptors, Tumor Necrosis Factor
- Transcriptome
- Up-Regulation