Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has received much attention owing to its ability to specifically induce cell death in cancer. However, several types of cancer, ...including some forms of breast cancer, are resistant to TRAIL. Various chemotherapeutic agents, phytochemicals, and TRAIL combination therapies have been proposed to resolve TRAIL resistance. Here, we explored the sensitization effect of birinapant on TRAIL-induced apoptosis in the MDA-MB-453 cell line. Although neither birinapant nor TRAIL showed any cytotoxic effect when used alone, apoptosis was induced when birinapant and TRAIL were used together. Our data suggest that the combination of birinapant and TRAIL induces downregulation of FLICE-like inhibitory protein (cFLIP) (L) protein expression. Interestingly, cFLIP(L) overexpression reversed apoptosis caused by co-treatment with TRAIL. Taken together, our results indicate that a combination of birinapant and TRAIL may be a promising treatment for TRAIL-resistant breast cancer.
•Treatment of Birinapant with TRAIL can lead to the apoptosis of TRAIL-resistance breast cancer cell lines.•cFLIP(L) is a key mediator of birinapant plus TRAIL-mediated apoptosis in MDA-MB-453 cell lines.•In other types of solid cancer, treatment with birinapant plus TRAIL induces apoptosis.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to selectively induce apoptotic cell death in various tumor cells by engaging its death-inducing receptors (TRAIL-R1 and ...TRAIL-R2). This property has led to the development of a number of TRAIL–receptor agonists such as the soluble recombinant TRAIL and agonistic antibodies, which have shown promising anticancer activity in preclinical studies. However, besides activating caspase-dependent apoptosis in several cancer cells, TRAIL may also activate nonapoptotic signal transduction pathways such as nuclear factor-kappa B, mitogen-activated protein kinases, AKT, and signal transducers and activators of transcription 3, which may contribute to TRAIL resistance that is being now frequently encountered in various cancers. TRAIL resistance can be overcome by the application of efficient TRAIL-sensitizing pharmacological agents. Natural compounds have shown a great potential in sensitizing cells to TRAIL treatment through suppression of distinct survival pathways. In this review, we have summarized both apoptotic and nonapoptotic pathways activated by TRAIL, as well as recent advances in developing TRAIL–receptor agonists for cancer therapy. We also briefly discuss combination therapies that have shown great potential in overcoming TRAIL resistance in various tumors.
Intracellular lipopolysaccharide from Gram-negative bacteria including Escherichia coli, Salmonella typhimurium, Shigella flexneri, and Burkholderia thailandensis activates mouse caspase-11, causing ...pyroptotic cell death, interleukin-1β processing, and lethal septic shock. How caspase-11 executes these downstream signalling events is largely unknown. Here we show that gasdermin D is essential for caspase-11-dependent pyroptosis and interleukin-1β maturation. A forward genetic screen with ethyl-N-nitrosourea-mutagenized mice links Gsdmd to the intracellular lipopolysaccharide response. Macrophages from Gsdmd(-/-) mice generated by gene targeting also exhibit defective pyroptosis and interleukin-1β secretion induced by cytoplasmic lipopolysaccharide or Gram-negative bacteria. In addition, Gsdmd(-/-) mice are protected from a lethal dose of lipopolysaccharide. Mechanistically, caspase-11 cleaves gasdermin D, and the resulting amino-terminal fragment promotes both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Our data identify gasdermin D as a critical target of caspase-11 and a key mediator of the host response against Gram-negative bacteria.
In Homo sapiens, the apoptosis‐inducing factor (AIF) family is represented by three different proteins, known as AIF, AMID and AIFL, that have in common the mitochondrial localisation in healthy ...cells, the presence of FAD‐ and NADH‐dependent domains involved in an ‐albeit yet not well understood‐ oxidoreductase function and their capability to induce programmed cell death. AIF is the best characterised family member, while the information about AMID and AIFL is much scarcer. Nonetheless, available data support different roles as well as mechanisms of action of their particular apoptogenic and redox domains regarding both pro‐apoptotic and anti‐apoptotic activities. Moreover, diverse cellular functions, to date far from fully clarified, are envisaged for the transcripts corresponding to these three proteins. Here, we review the so far available knowledge on the moonlighting human AIF family from their molecular properties to their relevance in health and disease, through the evaluation of their potential cell death and redox functions in their different subcellular locations. This picture emerging from the current knowledge of the AIF family envisages its contribution to regulate signalling and transcription machineries in the crosstalk among mitochondria, the cytoplasm and the nucleus.
Stem cell-based therapy is a promising intervention for ischemic heart diseases. However, the functional integrity of stem cells is impaired in an ischemic environment. Here, we report a novel ...finding that heat shock significantly improves Sca-1 super(+)stem cell survival in an ischemic environment by the regulation of the triangle: heat shock factor 1 (HSF1), HSF1/miR-34a, and heat shock protein 70 (HSP70). Initially we prove that HSP70 is the key chaperone-mediating cytoprotective effect of heat shock in Sca-1 super(+)cells and then we establish miR-34a as a direct repressor of HSP70. We found that HSP70 was downregulated in heat shocked Sca-1 super(+) stem cells ( super(HS)Sca-1 super(+) cells). Intriguingly, we demonstrate that the downregulation of miR-34a is attributed to HSF1-mediated epigenetic repression through histone H3 Lys27 trimethylation (H3K27me3) on miR-34a promoter. Moreover, we show that heat shock induces exosomal transfer of HSF1 from Sca-1 super(+) cells, which directs ischemic cardiomyocytes toward a prosurvival phenotype by epigenetic repression of miR-34a. In addition, our in vivo study demonstrates that transplantation of super(HS)Sca-1 super(+) cells significantly reduces apoptosis, attenuates fibrosis, and improves global heart functions in ischemic myocardium. Hence, our study provides not only novel insights into the effects of heat shock on stem cell survival and paracrine behavior but also may have therapeutic values for stem cell therapy in ischemic heart diseases. Stem Cells 2014; 32:462-472
Death receptors as targets in cancer Micheau, O; Shirley, S; Dufour, F
British journal of pharmacology,
August 2013, Letnik:
169, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Anti‐tumour therapies based on the use pro‐apoptotic receptor agonists, including TNF‐related apoptosis‐inducing ligand (TRAIL) or monoclonal antibodies targeting TRAIL‐R1 or TRAIL‐R2, have been ...disappointing so far, despite clear evidence of clinical activity and lack of adverse events for the vast majority of these compounds, whether combined or not with conventional or targeted anti‐cancer therapies. This brief review aims at discussing the possible reasons for the lack of apparent success of these therapeutic approaches and at providing hints in order to rationally design optimal protocols based on our current understanding of TRAIL signalling regulation or resistance for future clinical trials.
Linked Articles
This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue‐8
The Wnt/s-catenin pathway is a critical stem cell regulator and plays important roles in neuroepithelial cells during early gestation. However, the role of Wnt/s-catenin signaling in radial glia, a ...major neural stem cell population expanded by midgestation, remains poorly understood. This study shows that genetic ablation of s-catenin with hGFAP-Cre mice inhibits neocortical formation by disrupting radial glial development. Reduced radial glia and intermediate progenitors are found in the s-catenin-deficient neocortex during late gestation. Increased apoptosis and divergent localization of radial glia in the subventricular zone are also observed in the mutant neocortex. In vivo and in vitro proliferation and neurogenesis as well as oligodendrogenesis by cortical radial glia or by dissociated neural stem cells are significantly defective in the mutants. Neocortical layer patterning is not apparently altered, while astrogliogenesis is ectopically increased in the mutants. At the molecular level, the expression of the transcription factor Pax6 is dramatically diminished in the cortical radial glia and the sphere-forming neural stem cells of s-catenin-deficient mutants. Chromatin immunoprecipitation and luciferase assays demonstrate that s-catenin/Tcf complex binds to Pax6 promoter and induces its transcriptional activities. The forced expression of Pax6 through lentiviral transduction partially rescues the defective proliferation and neurogenesis by s-catenin-deficient neural stem cells. Thus, Pax6 is a novel downstream target of the Wnt/s-catenin pathway, and s-catenin/Pax6 signaling plays critical roles in self-renewal and neurogenesis of radial glia/neural stem cells during neocortical development. Stem Cells 2014; 32:45-58
Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) can induce apoptosis in a wide variety of cancer cells, both in vitro and in vivo, importantly without killing any essential ...normal cells. These findings formed the basis for the development of TRAIL-receptor agonists (TRAs) for cancer therapy. However, clinical trials conducted with different types of TRAs have, thus far, afforded only limited therapeutic benefit, as either the respectively chosen agonist showed insufficient anticancer activity or signs of toxicity, or the right TRAIL-comprising combination therapy was not employed. Therefore, in this review we will discuss molecular determinants of TRAIL resistance, the most promising TRAIL-sensitizing agents discovered to date and, importantly, whether any of these could also prove therapeutically efficacious upon cancer relapse following conventional first-line therapies. We will also discuss the more recent progress made with regards to the clinical development of highly active non-immunogenic next generation TRAs. Based thereupon, we next propose how TRAIL resistance might be successfully overcome, leading to the possible future development of highly potent, cancer-selective combination therapies that are based on our current understanding of biology TRAIL-induced cell death. It is possible that such therapies may offer the opportunity to tackle one of the major current obstacles to effective cancer therapy, namely overcoming chemo- and/or targeted-therapy resistance. Even if this were achievable only for certain types of therapy resistance and only for particular types of cancer, this would be a significant and meaningful achievement.
We reported a novel interaction between Beclin 1, a key regulator of autophagy, and survivin, a member of the inhibitor of apoptosis protein family. We found that knock-down of Beclin 1 ...down-regulated survivin protein, and the turnover rate of survivin was increased when Beclin 1 expression was silenced. Knock-down of Beclin 1 sensitized glioma cells to TRAIL-induced apoptosis, and introduction of survivin antagonized the sensitizing effect, suggesting that down-regulation of survivin mediates the enhanced sensitivity to TRAIL-induced apoptosis. These results demonstrate a novel interaction between Beclin 1 and survivin, and may provide a potential mechanism underlying the cross-talk between autophagy and apoptosis.
MINT-
7969366:
Beclin-1 (uniprotkb:
Q14457)
physically interacts (MI:
0915) with
survivin (uniprotkb:
O15392) by
anti tag coimmunoprecipitation (MI:
0007)
MINT-
7968986, MINT-
7969161:
survivin (uniprotkb:
O15392)
physically interacts (MI:
0915) with
Beclin-1 (uniprotkb:
Q14457) by
anti bait coimmunoprecipitation (MI:
0006)
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