NF-κB-dependent cytokine secretion controls Fas expression on chemotherapy-induced premature senescent tumor cells

Abstract

Induction of a senescent phenotype in tumor cells has been linked to anticancer immune response, however, the molecular mechanisms mediating these phenomenon have not yet been determined. In this study, we present evidence that induction of premature senescence in human cancer cell lines induces Fas expression, and loss of resistance to Fas-induced apoptosis. Triggering of Fas by using the agonistic antibody CH11 or the recombinant ligand APO010, activates an apoptotic pathway responsible for cell death. Secretion of pro-inflammatory cytokines by the senescent cells, particularly TNF-a and IFN-c, mediates Fas upregulation. Indeed, treatment of proliferating cancer cell lines with TNF-a and IFN-c, upregulates Fas expression, while blocking TNF-a and IFN-c by using neutralizing antibodies, decreases Fas expression in senescent cells. We also demonstrate that NF-jB has a central role in controlling the senescence-associated secretory phenotype (SASP) by the premature senescent cells, and that TNF-a and IFN-c, transcriptionally controlled by NF-jB, are the main mediators of Fas upregulation. Our data suggest the existence of an NF-jB-dependent autocrine loop, mediated by TNF-a and IFN-c, responsible for expression of Fas on the surface of senescent cells, and for their killing.

NF-κB Directly Regulates Fas Transcription to Modulate Fas-mediated Apoptosis and Tumor Suppression

“…More importantly, it has been shown that NF-B mediates recruitment of FADD and caspase 8 to the death-inducing signaling complex to increase tumor cell sensitivity to Fasmediated apoptosis in tumor cells (28). Furthermore, NF-B was found to regulate TNF␣ and IFN-␥ expression to up-regulate Fas expression (29). These studies thus demonstrate that NF-B mediates tumor cell sensitivity to Fas-mediated apoptosis.…”

“…4A). It has been shown that IFN-␥ and TNF␣, cytokines secreted by senescent tumor cells and activated immune cells, can up-regulate Fas expression (29,46,47). Indeed, IFN-␥ and TNF␣ synergistically up-regulated Fas in human colon carcinoma cells (Fig.…”

Impact of Recombinant Globular Adiponectin on Early Warm Ischemia-Reperfusion Injury in Rat Bile Duct after Liver Transplantation

“…In accordance with the findings from the TUNEL assay, our data showed that TNF-α was overexpressed during the early phase of WIRI whose expression could be significantly downregulated by pretreatment with APN. These data suggested that APN inhibited the activity of NF-κB (p65), consequently inhibiting the transcription of TNF-α1535.…”

Down-regulation of Wild-type p53-induced Phosphatase 1 (Wip1) Plays a Critical Role in Regulating Several p53-dependent Functions in Premature Senescent Tumor Cells

“…Senescent cells secrete growth factors, cytokines, and chemokines that affect both senescent cells and neighboring cells, functioning in an autocrine and/or paracrine mode (39,40). Notably, SASP occurs in vivo in response to DNA-damaging chemotherapy (11).…”