Special Issue "TRAIL Signaling in Cancer Cells"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (28 February 2019)

Special Issue Editor

Guest Editor
Dr. Olivier Micheau

INSERM UMR1231, Lipides Nutrition Cancer, UFR Sciences de Santé, UBFC, Université Bourgogne Franche-Comté, Dijon, France
Website | E-Mail
Interests: Apoptosis; TNF; TRAIL; Signaling; Cancer

Special Issue Information

Dear Colleagues,

Tumor necrosis factor–related apoptosis–inducing ligand (TRAIL) signal transduction has been associated, for many decades, with selective induction of apoptosis in cancer cells, prompting the clinical evaluation of several recombinant versions of this protein, antibodies targeting its agonist receptors, as well as TRAIL derivatives or inducing molecules, such as ONC201. Combining TRAIL or its derivatives with conventional chemotherapeutic drugs or chemical compounds derived from plant, fungi or marine sponge, to cite a few, often affords synergistic activation of apoptosis in tumor cells.

This paradigm is, however, challenged by recent findings highlighting the potentially harmful signaling capabilities of TRAIL, the activation of which can lead in some circumstances to cell motility and metastasis.

Identifying the molecular mechanisms governing TRAIL-induced pleiotropic signal transduction capabilities is likely to open novel therapeutic opportunities in oncology.

This Special Issue welcomes contributions related to TRAIL signal transduction regulation from the most fundamental aspects to its therapeutic exploitation.

Dr. Olivier Micheau
Guest Editor

Manuscript Submission Information

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Keywords

  • TRAIL
  • signal transduction
  • cancer
  • therapy
  • apoptosis
  • resistance
  • metastasis
  • cell motility

Published Papers (6 papers)

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Research

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Open AccessArticle MSC.sTRAIL Has Better Efficacy than MSC.FL-TRAIL and in Combination with AKTi Blocks Pro-Metastatic Cytokine Production in Prostate Cancer Cells
Cancers 2019, 11(4), 568; https://doi.org/10.3390/cancers11040568
Received: 4 March 2019 / Revised: 9 April 2019 / Accepted: 18 April 2019 / Published: 21 April 2019
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Abstract
Cell therapy is a promising new treatment option for cancer. In particular, mesenchymal stem cells (MSCs) have shown potential in delivering therapeutic genes in various tumour models and are now on the verge of being tested in the clinic. A number of therapeutic [...] Read more.
Cell therapy is a promising new treatment option for cancer. In particular, mesenchymal stem cells (MSCs) have shown potential in delivering therapeutic genes in various tumour models and are now on the verge of being tested in the clinic. A number of therapeutic genes have been examined in this context, including the death ligand TRAIL. For cell therapy, it can be used in its natural form as a full-length and membrane-bound protein (FL-TRAIL) or as an engineered version commonly referred to as soluble TRAIL (sTRAIL). As to which is more therapeutically efficacious, contradicting results have been reported. We discovered that MSCs producing sTRAIL have significantly higher apoptosis-inducing activity than cells expressing FL-TRAIL and found that FL-TRAIL, in contrast to sTRAIL, is not secreted. We also demonstrated that TRAIL does induce the expression of pro-metastatic cytokines in prostate cancer cells, but that this effect could be overcome through combination with an AKT inhibitor. Thus, a combination consisting of small-molecule drugs specifically targeting tumour cells in combination with MSC.sTRAIL, not only provides a way of sensitising cancer cells to TRAIL, but also reduces the issue of side-effect-causing cytokine production. This therapeutic strategy therefore represents a novel targeted treatment option for advanced prostate cancer and other difficult to treat tumours. Full article
(This article belongs to the Special Issue TRAIL Signaling in Cancer Cells)
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Open AccessArticle WP1130 Enhances TRAIL-Induced Apoptosis through USP9X-Dependent miR-708-Mediated Downregulation of c-FLIP
Cancers 2019, 11(3), 344; https://doi.org/10.3390/cancers11030344
Received: 8 February 2019 / Revised: 6 March 2019 / Accepted: 8 March 2019 / Published: 11 March 2019
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Abstract
WP1130, a partially selective deubiquitinases (DUB) inhibitor, inhibits the deubiquitinating activities of USP5, USP9X, USP14, USP37, and UCHL1. In this study, we investigate whether WP1130 exerts sensitizing effect on TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma cells. Combinations of WP1130 and [...] Read more.
WP1130, a partially selective deubiquitinases (DUB) inhibitor, inhibits the deubiquitinating activities of USP5, USP9X, USP14, USP37, and UCHL1. In this study, we investigate whether WP1130 exerts sensitizing effect on TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma cells. Combinations of WP1130 and TRAIL significantly induced apoptosis in renal carcinoma, lung carcinoma and hepatocellular carcinoma cells, but not in normal cells (human mesangial cells (MC) and normal mouse kidney cells (TCMK-1)). The downregulation of c-FLIP protein expression was involved in combined treatment-induced apoptosis. WP1130-induced c-FLIP downregulation was regulated by microRNA (miR)-708 upregulation via inhibition of USP9X. Interestingly, knockdown of USP9X markedly induced c-FLIP downregulation, upregulation of miR-708 expression and sensitivity to TRAIL. Furthermore, ectopic expression of USP9X prevented c-FLIP downregulation and apoptosis upon combined treatment. In sum, WP1130 sensitized TRAIL-induced apoptosis through miR-708-mediated downregulation of c-FLIP by inhibition of USP9X. Full article
(This article belongs to the Special Issue TRAIL Signaling in Cancer Cells)
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Open AccessArticle Circulating Tumor Cells Develop Resistance to TRAIL-Induced Apoptosis Through Autophagic Removal of Death Receptor 5: Evidence from an In Vitro Model
Received: 15 November 2018 / Revised: 8 January 2019 / Accepted: 8 January 2019 / Published: 15 January 2019
Cited by 2 | PDF Full-text (3904 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Circulating tumor cells (CTCs) in the peripheral blood are the precursors to distant metastasis but the underlying mechanisms are poorly understood. This study aims at understanding the molecular features within CTCs, in relation to their metastatic potential. Using in vitro CTC models, in [...] Read more.
Circulating tumor cells (CTCs) in the peripheral blood are the precursors to distant metastasis but the underlying mechanisms are poorly understood. This study aims at understanding the molecular features within CTCs, in relation to their metastatic potential. Using in vitro CTC models, in which breast cancer cell lines were cultured in non-adherent conditions simulating the microenvironment in the blood stream, we found that the suspension culture resulted in resistance to TNF-related apoptosis inducing ligand (TRAIL)-mediated cell death. Such a resistance was directly correlated with a reduction in surface and total levels of DR5 protein. In the non-adherent state, the cells underwent a rapid autophagic flux, characterized by an accumulation of autophagosome organelles. Notably, DR5 was translocated to the autophagosomes and underwent a lysosomal degradation. Our data suggest that CTCs may evade the TNF cytokine-mediated immune surveillance through a downregulation of the death receptor (DR) expression. The data warrants further studies in cancer patients to find the status of DRs and other molecular features within primary CTCs, in relation to disease progression or chemoresistance. Full article
(This article belongs to the Special Issue TRAIL Signaling in Cancer Cells)
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Review

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Open AccessReview TRAILblazing Strategies for Cancer Treatment
Cancers 2019, 11(4), 456; https://doi.org/10.3390/cancers11040456
Received: 11 March 2019 / Revised: 25 March 2019 / Accepted: 26 March 2019 / Published: 30 March 2019
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Abstract
In the late 1990s, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF-family, started receiving much attention for its potential in cancer therapy, due to its capacity to induce apoptosis selectively in tumour cells in vivo. TRAIL binds to its [...] Read more.
In the late 1990s, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF-family, started receiving much attention for its potential in cancer therapy, due to its capacity to induce apoptosis selectively in tumour cells in vivo. TRAIL binds to its membrane-bound death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) inducing the formation of a death-inducing signalling complex (DISC) thereby activating the apoptotic cascade. The ability of TRAIL to also induce apoptosis independently of p53 makes TRAIL a promising anticancer agent, especially in p53-mutated tumour entities. Thus, several so-called TRAIL receptor agonists (TRAs) were developed. Unfortunately, clinical testing of these TRAs did not reveal any significant anticancer activity, presumably due to inherent or acquired TRAIL resistance of most primary tumour cells. Since the potential power of TRAIL-based therapies still lies in TRAIL’s explicit cancer cell-selectivity, a desirable approach going forward for TRAIL-based cancer therapy is the identification of substances that sensitise tumour cells for TRAIL-induced apoptosis while sparing normal cells. Numerous of such TRAIL-sensitising strategies have been identified within the last decades. However, many of these approaches have not been verified in animal models, and therefore potential toxicity of these approaches has not been taken into consideration. Here, we critically summarise and discuss the status quo of TRAIL signalling in cancer cells and strategies to force tumour cells into undergoing apoptosis triggered by TRAIL as a cancer therapeutic approach. Moreover, we provide an overview and outlook on innovative and promising future TRAIL-based therapeutic strategies. Full article
(This article belongs to the Special Issue TRAIL Signaling in Cancer Cells)
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Open AccessFeature PaperReview Importance of TRAIL Molecular Anatomy in Receptor Oligomerization and Signaling. Implications for Cancer Therapy
Cancers 2019, 11(4), 444; https://doi.org/10.3390/cancers11040444
Received: 11 March 2019 / Revised: 25 March 2019 / Accepted: 26 March 2019 / Published: 29 March 2019
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Abstract
(TNF)-related apoptosis-inducing ligand (TRAIL) is able to activate the extrinsic apoptotic pathway upon binding to DR4/TRAIL-R1 and/or DR5/TRAIL-R2 receptors. Structural data indicate that TRAIL functions as a trimer that can engage three receptor molecules simultaneously, resulting in receptor trimerization and leading to conformational [...] Read more.
(TNF)-related apoptosis-inducing ligand (TRAIL) is able to activate the extrinsic apoptotic pathway upon binding to DR4/TRAIL-R1 and/or DR5/TRAIL-R2 receptors. Structural data indicate that TRAIL functions as a trimer that can engage three receptor molecules simultaneously, resulting in receptor trimerization and leading to conformational changes in TRAIL receptors. However, receptor conformational changes induced by the binding of TRAIL depend on the molecular form of this death ligand, and not always properly trigger the apoptotic cascade. In fact, TRAIL exhibits a much stronger pro-apoptotic activity when is found as a transmembrane protein than when it occurs as a soluble form and this enhanced biological activity is directly linked to its ability to cluster TRAIL receptors in supra-molecular structures. In this regard, cells involved in tumor immunosurveillance, such as activated human T cells, secrete endogenous TRAIL as a transmembrane protein associated with lipid microvesicles called exosomes upon T-cell reactivation. Consequently, it seems clear that a proper oligomerization of TRAIL receptors, which leads to a strong apoptotic signaling, is crucial for inducing apoptosis in cancer cells upon TRAIL treatment. In this review, the current knowledge of oligomerization status of TRAIL receptors is discussed as well as the implications for cancer treatment when using TRAIL-based therapies. Full article
(This article belongs to the Special Issue TRAIL Signaling in Cancer Cells)
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Open AccessReview Emerging Therapies for Acute Myelogenus Leukemia Patients Targeting Apoptosis and Mitochondrial Metabolism
Cancers 2019, 11(2), 260; https://doi.org/10.3390/cancers11020260
Received: 28 January 2019 / Accepted: 14 February 2019 / Published: 22 February 2019
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Abstract
Acute Myelogenous Leukemia (AML) is a malignant disease of the hematopoietic cells, characterized by impaired differentiation and uncontrolled clonal expansion of myeloid progenitors/precursors, resulting in bone marrow failure and impaired normal hematopoiesis. AML comprises a heterogeneous group of malignancies, characterized by a combination [...] Read more.
Acute Myelogenous Leukemia (AML) is a malignant disease of the hematopoietic cells, characterized by impaired differentiation and uncontrolled clonal expansion of myeloid progenitors/precursors, resulting in bone marrow failure and impaired normal hematopoiesis. AML comprises a heterogeneous group of malignancies, characterized by a combination of different somatic genetic abnormalities, some of which act as events driving leukemic development. Studies carried out in the last years have shown that AML cells invariably have abnormalities in one or more apoptotic pathways and have identified some components of the apoptotic pathway that can be targeted by specific drugs. Clinical results deriving from studies using B-cell lymphoma 2 (BCL-2) inhibitors in combination with standard AML agents, such as azacytidine, decitabine, low-dose cytarabine, provided promising results and strongly support the use of these agents in the treatment of AML patients, particularly of elderly patients. TNF-related apoptosis-inducing ligand (TRAIL) and its receptors are frequently deregulated in AML patients and their targeting may represent a promising strategy for development of new treatments. Altered mitochondrial metabolism is a common feature of AML cells, as supported through the discovery of mutations in the isocitrate dehydrogenase gene and in mitochondrial electron transport chain and of numerous abnormalities of oxidative metabolism existing in AML subgroups. Overall, these observations strongly support the view that the targeting of mitochondrial apoptotic or metabolic machinery is an appealing new therapeutic perspective in AML. Full article
(This article belongs to the Special Issue TRAIL Signaling in Cancer Cells)
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