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Release of c-FLIP brake selectively sensitizes human cancer cells to TLR3-mediated apoptosis.

ABSTRACT: Toll-like receptor 3 (TLR3) mediates innate immune responses by sensing viral dsRNA, but also induces apoptosis selectively in cancer cells. Our analysis by immunohistochemistry revealed that TLR3 is frequently overexpressed in 130 non-small cell lung cancer (NSCLC) patients' samples compared with normal bronchial epithelium (P?

SUBMITTER: Alkurdi L

PROVIDER: S-EPMC6115461 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Release of c-FLIP brake selectively sensitizes human cancer cells to TLR3-mediated apoptosis.

Alkurdi Lugain L Virard François F Vanbervliet Béatrice B Weber Kathrin K Toscano Florent F Bonnin Marc M Le Stang Nolwenn N Lantuejoul Sylvie S Micheau Olivier O Renno Toufic T Lebecque Serge S Estornes Yann Y Estornes Yann Y

Cell death & disease 20180829 9

Toll-like receptor 3 (TLR3) mediates innate immune responses by sensing viral dsRNA, but also induces apoptosis selectively in cancer cells. Our analysis by immunohistochemistry revealed that TLR3 is frequently overexpressed in 130 non-small cell lung cancer (NSCLC) patients' samples compared with normal bronchial epithelium (P < 0.0001, Mann-Whitney test), supporting the therapeutic potential of TLR3 ligand for this type of cancer. However, a proportion of TLR3-expressing cancer cell lines, inc ...[more]

PMID: 30158588

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IL-24 sensitizes tumor cells to TLR3-mediated apoptosis.

Project description:Interleukin-24 (IL-24), a member of the IL-10 cytokine family whose physiological function remains largely unknown, has been shown to induce apoptosis when expressed in an adenoviral background. It is yet little understood, why IL-24 alone induced apoptosis only in a limited number of tumor cell lines. Analyzing an influenza A virus vector expressing IL-24 for its oncolytic potential revealed enhanced pro-apoptotic activity of the chimeric virus compared with virus or IL-24 alone. Interestingly, IL-24-mediated enhancement of influenza-A-induced apoptosis did not require viral replication but critically depended on toll-like receptor 3 (TLR3) and caspase-8. Immunoprecipitation of TLR3 showed that infection by influenza A virus induced formation of a TLR3-associated signaling complex containing TRIF, RIP1, FADD, cFLIP and pro-caspase-8. Co-administration of IL-24 decreased the presence of cFLIP in the TLR3-associated complex, converting it into an atypical, TLR3-associated death-inducing signaling complex (TLR3 DISC) that induced apoptosis by enabling caspase-8 activation at this complex. The sensitizing effect of IL-24 on TLR3-induced apoptosis, mediated by influenza A virus or the TLR3-specific agonist poly(I:C), was also evident on tumor spheroids. In conclusion, rather than acting as an apoptosis inducer itself, IL-24 sensitizes cancer cells to TLR-mediated apoptosis by enabling the formation of an atypical DISC which, in the case of influenza A virus or poly(I:C), is associated with TLR3.

| S-EPMC3647237 | biostudies-literature

Helicobacter pylori sensitizes TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human gastric epithelial cells through regulation of FLIP.

Project description:Helicobacter pylori (H. pylori) infection is associated with chronic gastritis, peptic ulcer and gastric cancer. Apoptosis induced by microbial infections is implicated in the pathogenesis of H. pylori infection. Here we show that human gastric epithelial cells sensitized to H. pylori confer susceptibility to TRAIL-mediated apoptosis via modulation of death receptor signaling. Human gastric epithelial cells are intrinsically resistant to TRAIL-mediated apoptosis. The induction of TRAIL sensitivity by H. pylori is dependent on the activation of caspase-8 and its downstream pathway. H. pylori induces caspase-8 activation via enhanced assembly of the TRAIL death-inducing signaling complex (DISC) through downregulation of cellular FLICE-inhibitory protein (FLIP). Overexpression of FLIP abolished the H. pylori-induced TRAIL sensitivity in human gastric epithelial cells. Our study thus demonstrates that H. pylori induces sensitivity to TRAIL apoptosis by regulation of FLIP and assembly of DISC, which initiates caspase activation, resulting in the breakdown of resistance to apoptosis, and provides insight into the pathogenesis of gastric damage in Helicobacter infection. Modulation of host apoptosis signaling by bacterial interaction adds a new dimension to the pathogenesis of Helicobacter.

| S-EPMC3973194 | biostudies-other

Vitamin E δ-tocotrienol sensitizes human pancreatic cancer cells to TRAIL-induced apoptosis through proteasome-mediated down-regulation of c-FLIP<sub>s</sub>.

Project description:BackgroundVitamin E δ-tocotrienol (VEDT), a vitamin E compound isolated from sources such as palm fruit and annatto beans, has been reported to have cancer chemopreventive and therapeutic effects.MethodsWe report a novel function of VEDT in augmenting tumor necrosis factor-related apoptosis-inducing ligand- (TRAIL-) induced apoptosis in pancreatic cancer cells. The effects of VEDT were shown by its ability to trigger caspase-8-dependent apoptosis in pancreatic cancer cells.ResultsWhen combined with TRAIL, VEDT significantly augmented TRAIL-induced apoptosis of pancreatic cancer cells. VEDT decreased cellular FLICE inhibitory protein (c-FLIP) levels without consistently modulating the expression of decoy death receptors 1, 2, 3 or death receptors 4 and 5. Enforced expression of c-FLIP substantially attenuated VEDT/TRAIL-induced apoptosis. Thus, c-FLIP reduction plays an important part in mediating VEDT/TRAIL-induced apoptosis. Moreover, VEDT increased c-FLIP ubiquitination and degradation but did not affect its transcription, suggesting that VEDT decreases c-FLIP levels through promoting its degradation. Of note, degradation of c-FLIP and enhanced TRAIL-induced apoptosis in pancreatic cancer cells were observed only with the anticancer bioactive vitamin E compounds δ-, γ-, and β-tocotrienol but not with the anticancer inactive vitamin E compounds α-tocotrienol and α-, β-, γ-, and δ-tocopherol.Conclusionsc-FLIP degradation is a key event for death receptor-induced apoptosis by anticancer bioactive vitamin E compounds in pancreatic cancer cells. Moreover, VEDT augmented TRAIL inhibition of pancreatic tumor growth and induction of apoptosis in vivo. Combination therapy with TRAIL agonists and bioactive vitamin E compounds may offer a novel strategy for pancreatic cancer intervention.

| S-EPMC6647259 | biostudies-literature

Bufalin sensitizes human bladder carcinoma cells to TRAIL-mediated apoptosis.

Project description:Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, has garnered interest as it is relatively non-toxic to normal cells, but selectively induces apoptotic cell death in multiple types of transformed or malignant cells. Bufalin is the major digoxin-like immunoreactive component of Sum Su, which is obtained from the skin and parotid venom gland of the toad. Bufalin is known to inhibit cell proliferation and induce apoptosis in a variety of cancer cells. The present study investigated whether bufalin promoted TRAIL-induced apoptotic cell death. In the present study, a combined treatment using bufalin and TRAIL significantly increased TRAIL-mediated inhibition of cell viability and increased apoptosis in T24 human bladder cancer cells. The apoptotic effects were associated with the upregulation of death receptor proteins and the downregulation of cellular Fas-associated death domain-like interleukin-1β-converting enzyme inhibitory protein and X-linked inhibitor of apoptosis protein. Furthermore, the data revealed that bufalin and TRAIL activated caspase-3, -8 and -9 and subsequently increased the degradation of poly (ADP-ribose) polymerase. Taken altogether, the nontoxic doses of bufalin and TRAIL sensitized T24 cells to TRAIL-mediated apoptosis. Therefore, bufalin may provide an effective therapeutic strategy for the safe treatment of human bladder cancers that are resistant to TRAIL.

| S-EPMC5494769 | biostudies-other

Downregulation of c‑FLIP and upregulation of DR‑5 by cantharidin sensitizes TRAIL‑mediated apoptosis in prostate cancer cells via autophagy flux.

Project description:Tumor necrosis factor (TNF)‑related apoptosis‑inducing ligand (TRAIL), a type II transmembrane protein, is a part of the TNF superfamily of cytokines. Cantharidin, a type of terpenoid, is extracted from the blister beetles (Mylabris genus) used in Traditional Chinese Medicine. Cantharidin elicits antibiotic, antiviral and antitumor effects, and can affect the immune response. The present study demonstrated that a cantharidin and TRAIL combination treatment regimen elicited a synergistic outcome in TRAIL‑resistant DU145 cells. Notably, it was also identified that cantharidin treatment initiated the downregulation of cellular FLICE‑like inhibitory protein (c‑FLIP) and upregulation of death receptor 5 (DR‑5), and sensitized cells to TRAIL‑mediated apoptosis by initiating autophagy flux. In addition, cantharidin treatment increased lipid‑modified microtubule‑associated proteins 1A/1B light chain 3B expression and significantly attenuated sequestosome 1 expression. Attenuation of autophagy flux by a specific inhibitor such as chloroquine and genetic modification using ATG5 small interfering RNA abrogated the cantharidin‑mediated TRAIL‑induced apoptosis. Overall, the results of the present study revealed that cantharidin effectively sensitized cells to TRAIL‑mediated apoptosis and its effects are likely to be mediated by autophagy, the downregulation of c‑FLIP and the upregulation of DR‑5. They also suggested that the combination of cantharidin and TRAIL may be a successful therapeutic strategy for TRAIL‑resistant prostate cancer.

| S-EPMC7255450 | biostudies-literature

PAX3-FKHR sensitizes human alveolar rhabdomyosarcoma cells to camptothecin-mediated growth inhibition and apoptosis.

Project description:Patients with alveolar rhabdomyosarcoma (ARMS) have poorer response to conventional chemotherapy and lower survival rates than those with embryonal RMS (ERMS). By high-throughput screening, we identified camptothecin as an ARMS-selective inhibitor. Camptothecin more efficiently inhibited proliferation and induced apoptosis in Rh30 (ARMS) than RD (ERMS) cells. Ectopic expression of the PAX3-FKHR (PF) fusion protein in RD cells significantly increased sensitivity, whereas siRNA knockdown of PF decreased sensitivity of Rh30 cells to camptothecin. The sensitization required a transcriptionally active PF, and camptothecin downregulated levels of PF protein. These findings suggest that it is feasible to develop agents that preferentially block the growth of ARMS.

| S-EPMC2739888 | biostudies-literature

DRO1 sensitizes colorectal cancer cells to receptor-mediated apoptosis.

Project description:The molecule DRO1 (down‑regulated by oncogenes 1) is a potential tumor suppressor protein that is frequently down‑regulated in primary colorectal cancers and colorectal cancer cell lines. Although the mechanism of DRO1 action has yet to be elucidated, previous data have suggested that DRO1 interferes with tumor growth by sensitizing cells to apoptosis. The effect of DRO1 expression on receptor-, mitochondrial- and endoplasmic reticulum‑mediated apoptosis in colorectal cancer cell lines was analyzed in this study, following the generation of DLD1/DRO1 and HCT116/DRO1 cell lines. Cells were cultured, and then analyzed using flow cytometry. DRO1 was found to sensitize cells to receptor-mediated apoptosis by promoting the activation of components of the death-inducing signaling complex (DISC).

| S-EPMC3408059 | biostudies-literature

The contact allergen nickel sensitizes primary human endothelial cells and keratinocytes to TRAIL-mediated apoptosis.

Project description:Primary endothelial cells are fully resistant to TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Here, we demonstrate that certain environmental conditions, such as exposure to the widespread allergen nickel, can dramatically increase the susceptibility of naturally resistant primary endothelial cells or keratinocytes to TRAIL-induced apoptosis. While nickel treatment increased surface expression of the apoptosis-inducing TRAIL receptors TRAIL-R1 and TRAIL-R2, it also up-regulated the apoptosis-deficient TRAIL-R4, suggesting that modulation of TRAIL receptor expression alone is unlikely to fully account for the dramatic sensitization effect of nickel. Further analysis of candidate mediators revealed that nickel strongly repressed c-FLIP at mRNA and protein levels. Accordingly, increased activation of Caspase-8 and Caspase-3 following nickel treatment was observed. Importantly, depletion of c-FLIP by RNA interference could largely recapitulate the effect of nickel and sensitize endothelial cells to TRAIL-dependent apoptosis in the absence of nickel pre-treatment. Conversely, ectopic expression of c-FLIP(L) largely protected nickel-treated cells from TRAIL-mediated apoptosis. Our data demonstrate that one key mechanism of sensitization of primary human endothelial cells or keratinocytes is transcriptional down-regulation of c-FLIP. We hypothesize that environmental factors, exemplified by the contact allergen nickel, strongly modulate death ligand sensitivity of endothelial cells and keratinocytes thus influencing vascular and epidermal function and integrity under physiological and pathophysiological conditions.

| S-EPMC3829037 | biostudies-literature

YM155 sensitizes TRAIL-induced apoptosis through cathepsin S-dependent down-regulation of Mcl-1 and NF-κB-mediated down-regulation of c-FLIP expression in human renal carcinoma Caki cells.

Project description:YM155, a small-molecule survivin inhibitor, has been reported for its anti-cancer activity in various cancer cells. In this study, we investigated the effect of YM155 to enhance TRAIL-mediated apoptosis in human renal carcinoma cells. We found that YM155 alone had no effect on apoptosis, however, combined treatment with YM155 and TRAIL markedly induced apoptosis in human renal carcinoma cells (Caki, ACHN, and A498), breast cancer cells (MDA-MB231), and glioma cells (U251MG), but not normal cells [mesangial cell (MC) and human skin fibroblast (HSF)]. YM155 induced down-regulation of Mcl-1 expression at the post-translational levels, and the overexpression of Mcl-1 markedly inhibited YM155 plus TRAIL-induced apoptosis. Furthermore, YM155 induced down-regulation of c-FLIP mRNA expression through inhibition of NF-κB transcriptional activity. Ectopic expression of c-FLIP markedly blocked YM155-induced TRAIL sensitization. Taken together, our results suggested that YM155 sensitizes TRAIL-mediated apoptosis via down-regulation of Mcl-1 and c-FLIP expression in renal carcinoma Caki cells.

| S-EPMC5308669 | biostudies-literature

Extracellular Nucleotides and Histamine Suppress TLR3- and RIG-I-Mediated Release of Antiviral IFNs from Human Airway Epithelial Cells.

Project description:Respiratory viruses stimulate the release of antiviral IFNs from the airway epithelium. Previous studies have shown that asthmatic patients show diminished release of type I and type III IFNs from bronchial epithelia. However, the mechanism of this suppression is not understood. In this study, we report that extracellular nucleotides and histamine, which are elevated in asthmatic airways, strongly inhibit release of type I and type III IFNs from human bronchial airway epithelial cells (AECs). Specifically, ATP, UTP, and histamine all inhibited the release of type I and type III IFNs from AECs induced by activation of TLR3, retinoic acid-inducible gene I (RIG-I), or cyclic GMP-AMP synthase-STING. This inhibition was at least partly mediated by Gq signaling through purinergic P2Y2 and H1 receptors, but it did not involve store-operated calcium entry. Pharmacological blockade of protein kinase C partially reversed inhibition of IFN production. Conversely, direct activation of protein kinase C with phorbol esters strongly inhibited TLR3- and RIG-I-mediated IFN production. Inhibition of type I and type III IFNs by ATP, UTP, histamine, and the proteinase-activated receptor 2 (PAR2) receptor agonist SLIGKV also occurred in differentiated AECs grown at an air-liquid interface, indicating that the suppression is conserved following mucociliary differentiation. Importantly, histamine and, more strikingly, ATP inhibited type I IFN release from human airway cells infected with live influenza A virus or rhinovirus 1B. These results reveal an important role for extracellular nucleotides and histamine in attenuating the induction of type I and III IFNs from AECs and help explain the molecular basis of the suppression of IFN responses in asthmatic patients.

| S-EPMC9444327 | biostudies-literature

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