Soluble TNF-like weak inducer of apoptosis (TWEAK) enhances poly(I:C)-induced RIPK1-mediated necroptosis

Abstract

TNF-like weak inducer of apoptosis (TWEAK) and inhibition of protein synthesis with cycloheximide (CHX) sensitize for poly(I:C)-induced cell death. Notably, although CHX preferentially enhanced poly(I:C)-induced apoptosis, TWEAK enhanced primarily poly(I:C)-induced necroptosis. Both sensitizers of poly(I:C)-induced cell death, however, showed no major effect on proinflammatory poly(I:C) signaling. Analysis of a panel of HeLa-RIPK3 variants lacking TRADD, RIPK1, FADD, or caspase-8 expression revealed furthermore similarities and differences in the way how poly(I:C)/TWEAK, TNF, and TRAIL utilize these molecules for signaling. RIPK1 turned out to be essential for poly(I:C)/TWEAK-induced caspase-8-mediated apoptosis but was dispensable for this response in TNF and TRAIL signaling. TRADD-RIPK1-double deficiency differentially affected poly(I:C)-triggered gene induction but abrogated gene induction by TNF completely. FADD deficiency abrogated TRAIL- but not TNF- and poly(I:C)-induced necroptosis, whereas TRADD elicited protective activity against all three death inducers. A general protective activity against poly(I:C)-, TRAIL-, and TNF-induced cell death was also observed in FLIPL and FLIPS transfectrants.

Bioactive Brominated Oxindole Alkaloids from the Red Sea Sponge Callyspongia siphonella

“…Moreover, 1 was not able to induce the upregulation of proinflammatory cytokines such as interleukin-8 (IL8) in MM.1S and HT-29 (Figure S2, Supplementary Materials). Our previous results and many previous publications showed that the programmed cell death is usually accompanied by the induction of proinflammatory signals such as IL8 [31,32]. This confirms the Western blotting results that compound 1 kills the cancer cells by non-programmed cell necrosis but not by programmed cell death mechanisms such as necroptosis, apoptosis, or autophagy.…”

“…In the next day, cells were harvested in ice-cold PBS and washed by centrifuging cells twice in PBS and centrifuged for 4 min at 1200 rpm (4°C). Then, total cell lysates were prepared as described before in our previous work [32]. The membranes were incubated overnight with primary antibodies and antigen-antibody reactions were performed in the next day using the corresponding secondary antibodies (anti-mouse-HRP, Dako-Cytomation, Hamburg, Germany; anti-rabbit-HRP, Cell Signaling Technology).…”

TWEAK Promotes the Proliferation of Squamous Cell Carcinoma Cells Through Activating cIAP1 Signals

“…Both TWEAK and TRAIL are members of TNF superfamily, and act differentially or cooperate in regulating cancer cells (16). Our results demonstrated that the mRNA expression levels of TRAIL receptor type 1 (TRAIL-R1) and TRAIL-R2 were not affected in SCC-13 cells by TWEAK stimulation (0 to 1000 ng/ml) while both TRAIL-R3 and TRAIL-R4 increased with the increase of TWEAK dose (Figure 4A).…”

“…Both TWEAK and TRAIL are members of TNF superfamily, and act differentially or cooperate in regulating various cells (16,28,29). There are four types of TRAIL-Rs, including TRAIL-R1, TRAIL-R2, TRAIL-R3, and TRAIL-R4.…”

The Selection of NFκB Inhibitors to Block Inflammation and Induce Sensitisation to FasL-Induced Apoptosis in HNSCC Cell Lines Is Critical for Their Use as a Prospective Cancer Therapy

“…Inhibition of the NFκB pathway can lead to altered homeostasis of anti- and pro-apoptotic genes and render the inflammatory factor TNFα, a death ligand, which triggers apoptosis [40,41,42]. The classical experiment involved the incubation of cell lines (e.g., HaCaT) [43] with the antibiotic cycloheximide (CHX). CHX attacks ribosomes, inhibiting de novo protein synthesis and leading to cFLIP inhibition.…”