RESUMEN
The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) initiates the extrinsic apoptotic pathway through formation of the death-inducing signaling complex (DISC), followed by activation of effector caspases. TRAIL receptors are composed of death receptors (DR4 and DR5), decoy receptors (DcR1 and DcR2), and osteoprotegerin. Among them, only DRs activate apoptotic signaling by TRAIL. Since the levels of DR expressions are higher in cancer cells than in normal cells, TRAIL selectively activates apoptotic signaling pathway in cancer cells. However, multiple mechanisms, including down-regulation of DR expression and pro-apoptotic proteins, and up-regulation of anti-apoptotic proteins, make cancer cells TRAIL-resistant. Therefore, many researchers have investigated strategies to overcome TRAIL resistance. In this review, we focus on protein regulation in relation to extrinsic apoptotic signaling pathways via ubiquitination. The ubiquitin proteasome system (UPS) is an important process in control of protein degradation and stabilization, and regulates proliferation and apoptosis in cancer cells. The level of ubiquitination of proteins is determined by the balance of E3 ubiquitin ligases and deubiquitinases (DUBs), which determine protein stability. Regulation of the UPS may be an attractive target for enhancement of TRAIL-induced apoptosis. Our review provides insight to increasing sensitivity to TRAIL-mediated apoptosis through control of post-translational protein expression. [BMB Reports 2019; 52(2): 119-126].
Asunto(s)
Apoptosis/fisiología , Enzimas Desubicuitinizantes/fisiología , Ubiquitina-Proteína Ligasas/fisiología , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Portadoras/metabolismo , Caspasas/metabolismo , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/metabolismo , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/fisiología , Humanos , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/fisiología , Transducción de Señal , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/fisiología , Receptores Señuelo del Factor de Necrosis Tumoral/fisiología , Factor de Necrosis Tumoral alfa/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Poly(ADP-ribose) polymerase-13 (PARP13/ZAP/ZC3HAV1) is an antiviral factor, active against specific RNA viruses such as murine leukaemia virus, Sindbis virus and human immunodeficiency virus. During infection, PARP13 binds viral RNA via its four CCCH-type zinc-finger domains and targets it for degradation by recruiting cellular messenger RNA (mRNA) decay factors such as the exosome complex and XRN1. Here we show that PARP13 binds to and regulates cellular mRNAs in the absence of viral infection. Knockdown of PARP13 results in the misregulation of hundreds of transcripts. Among the most upregulated transcripts is TRAILR4 that encodes a decoy receptor for TRAIL-a pro-apoptotic cytokine that is a promising target for the therapeutic inhibition of cancers. PARP13 destabilizes TRAILR4 mRNA post-transcriptionally in an exosome-dependent manner by binding to a region in its 3' untranslated region. As a consequence, PARP13 represses TRAILR4 expression and increases cell sensitivity to TRAIL-mediated apoptosis, acting as a key regulator of the cellular response to TRAIL.
Asunto(s)
Apoptosis/fisiología , Procesamiento Postranscripcional del ARN/fisiología , ARN Mensajero/fisiología , Proteínas de Unión al ARN/fisiología , Transcripción Genética/fisiología , Receptores Señuelo del Factor de Necrosis Tumoral/fisiología , Apoptosis/genética , Línea Celular , Exosomas/genética , Exosomas/fisiología , Técnicas de Inactivación de Genes , Células HeLa , Humanos , Procesamiento Postranscripcional del ARN/genética , ARN Mensajero/genética , Proteínas de Unión al ARN/genética , Transcripción Genética/genética , Transcriptoma/genética , Transcriptoma/fisiología , Receptores Señuelo del Factor de Necrosis Tumoral/genética , Dedos de Zinc/genética , Dedos de Zinc/fisiologíaRESUMEN
Experimental autoimmune uveoretinitis is an autoimmune disease induced in mice, which involves the infiltration of CD11b(+) macrophages and CD4(+) T cells into the normally immune-privileged retina. Damage is produced in the target organ following the activation of Th1 and Th17 T cells and by the release of cytotoxic mediators such as NO by activated macrophages. The majority of immune cells infiltrating into the retina are CD11b(+) myeloid cells, but, despite the presence of these APCs, relatively limited numbers of T cells are observed in the retina during the disease course. These T cells do not proliferate when leukocytes are isolated from the retina and restimulated in vitro, although they do produce both IFN-gamma and IL-17. T cell proliferation was restored by depleting the myeloid cells from the cultures and furthermore those isolated myeloid cells were able to regulate the proliferation of other T cells. The ability of macrophages to regulate proliferation depends on activation by T cell-produced IFN-gamma and autocrine TNF-alpha signaling in the myeloid cells via TNFR1. In the absence of TNFR1 signaling, relative T cell expansion in the retina is increased, indicating that regulatory myeloid cells may also act in vivo. However, TNFR1 signaling is also required for macrophages, but not T cells, to migrate into the target organ. Thus, in TNFR1 knock out mice, the amplification of autoimmunity is limited, leading to resistance to experimental autoimmune uveoretinitis induction.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Células Mieloides/inmunología , Receptores Tipo I de Factores de Necrosis Tumoral/fisiología , Retinitis/inmunología , Retinitis/patología , Uveítis/inmunología , Uveítis/patología , Secuencia de Aminoácidos , Animales , Enfermedades Autoinmunes/genética , Movimiento Celular/genética , Movimiento Celular/inmunología , Células Cultivadas , Femenino , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Datos de Secuencia Molecular , Células Mieloides/metabolismo , Células Mieloides/patología , Receptores Tipo I de Factores de Necrosis Tumoral/deficiencia , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Retinitis/genética , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Receptores Señuelo del Factor de Necrosis Tumoral/deficiencia , Receptores Señuelo del Factor de Necrosis Tumoral/genética , Receptores Señuelo del Factor de Necrosis Tumoral/fisiología , Uveítis/genéticaRESUMEN
In order to examine the role of IFN-gamma, TNFRp55 and iNOS in inflammatory reaction during toxoplasmosis, IFN-gamma(-/-), TNFRp55(-/-) and iNOS(-/-) mice were experimentally infected with Toxoplasma gondii ME-49 strain. The organs of the mice were evaluated for histology and immunohistochemistry in detection of tissue parasitism and iNOS positive cells. IFN-gamma(-/-) mice presented mild inflammation in peripheral organs associated with a high parasitism and mortality in the acute phase of infection. In contrast, the peripheral organs of WT, TNFRp55(-/-) and iNOS(-/-) mice, presented a significant inflammatory reaction and low tissue parasitism in the same period of infection. The inflammatory lesions and tissue parasitism were increased and more severe in the Central Nervous System (CNS) of TNFRp55(-/-) and iNOS(-/-) with a progression of infection, when compared to WT mice. In these knockout animals, the inflammatory changes were associated with low levels or no expression of iNOS in TNFRp55(-/-) and iNOS(-/-) mice, respectively.
Asunto(s)
Interferón gamma/fisiología , Óxido Nítrico Sintasa de Tipo II/fisiología , Receptores Tipo I de Factores de Necrosis Tumoral/fisiología , Toxoplasma/fisiología , Toxoplasmosis Animal/inmunología , Receptores Señuelo del Factor de Necrosis Tumoral/fisiología , Animales , Encéfalo/parasitología , Corazón/parasitología , Inmunohistoquímica , Inflamación/inmunología , Hígado/parasitología , Pulmón/parasitología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Médula Espinal/parasitología , Bazo/parasitología , Toxoplasmosis Animal/patologíaRESUMEN
Tumour necrosis factor-related apoptosis-inducing ligand or Apo2 ligand (TRAIL/Apo2L) is a member of the tumour necrosis factor (TNF) superfamily of cytokines that induces apoptosis upon binding to its death domain-containing transmembrane receptors, death receptors 4 and 5 (DR4, DR5). Importantly, TRAIL preferentially induces apoptosis in cancer cells while exhibiting little or no toxicity in normal cells. To date, research has focused on the mechanism of apoptosis induced by TRAIL and the processes involved in the development of TRAIL resistance. TRAIL-resistant tumours can be re-sensitized to TRAIL by a combination of TRAIL with chemotherapeutics or irradiation. Studies suggest that in many cancer cells only one of the two death-inducing TRAIL receptors is functional. These findings as well as the aim to avoid decoy receptor-mediated neutralization of TRAIL led to the development of receptor-specific TRAIL variants and agonistic antibodies. These molecules are predicted to be more potent than native TRAIL in vivo and may be suitable for targeted treatment of particular tumours. This review focuses on the current status of TRAIL receptor-targeting for cancer therapy, the apoptotic signalling pathway induced by TRAIL receptors, the prognostic implications of TRAIL receptor expression and modulation of TRAIL sensitivity of tumour cells by combination therapies. The mechanisms of TRAIL resistance and the potential measures that can be taken to overcome them are also addressed. Finally, the status of clinical trials of recombinant TRAIL and DR4-/DR5-specific agonistic antibodies as well as the pre-clinical studies of receptor-selective TRAIL variants is discussed including the obstacles facing the use of these molecules as anti-cancer therapeutics.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/fisiología , Proteínas de Neoplasias/fisiología , Neoplasias/terapia , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/fisiología , Receptores del Factor de Necrosis Tumoral/fisiología , Ligando Inductor de Apoptosis Relacionado con TNF/fisiología , Receptores Señuelo del Factor de Necrosis Tumoral/fisiología , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/fisiología , Ensayos Clínicos como Asunto/estadística & datos numéricos , Terapia Combinada , Sistemas de Liberación de Medicamentos , Resistencia a Antineoplásicos , Proteínas Ligadas a GPI , Humanos , Proteínas de Neoplasias/agonistas , Proteínas de Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/radioterapia , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/agonistas , Receptores del Factor de Necrosis Tumoral/agonistas , Miembro 10c de Receptores del Factor de Necrosis Tumoral , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Transducción de Señal/efectos de los fármacos , Ligando Inductor de Apoptosis Relacionado con TNF/agonistas , Ligando Inductor de Apoptosis Relacionado con TNF/inmunología , Ligando Inductor de Apoptosis Relacionado con TNF/uso terapéutico , Receptores Señuelo del Factor de Necrosis Tumoral/agonistas , Receptores Señuelo del Factor de Necrosis Tumoral/inmunología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The use of trovafloxacin (TVX), a fluoroquinolone antibiotic, was severely restricted because of an association of TVX therapy with idiosyncratic hepatotoxicity in patients. The mechanisms underlying idiosyncratic toxicity are unknown; however, one hypothesis is that an inflammatory stress can render an individual sensitive to the drug. Previously, we reported that treatment of mice with TVX and lipopolysaccharide (LPS) induced tumor necrosis factor (TNF) alpha-dependent liver injury, whereas TVX or LPS treatment alone was nontoxic. The goal of this study was to elucidate the role of TNFalpha in TVX/LPS-induced liver injury. TNF receptor (TNFR) 1 p55(-/-) and TNFR2 (p75(-/-)) mice were protected from hepatotoxicity caused by TVX/LPS coexposure, suggesting that TVX/LPS-induced liver injury requires both TNF receptors. TNFalpha inhibition using etanercept significantly reduced the TVX/LPS-induced increases in the plasma concentrations of several cytokines around the time of onset of liver injury. However, despite the reduction in chemokines, etanercept treatment did not affect the TVX/LPS-induced hepatic accumulation of neutrophils. In addition, etanercept treatment attenuated TVX/LPS induction of plasminogen activator inhibitor-1, and this was associated with a reduction in hepatic fibrin deposition. Mice treated with TVX and a nontoxic dose of TNFalpha also developed liver injury. In summary, TNFalpha acts through p55 and p75 receptors to precipitate an innocuous inflammatory cascade. TVX enhances this cascade, converting it into one that results in hepatocellular injury.
Asunto(s)
Fluoroquinolonas/toxicidad , Lipopolisacáridos/toxicidad , Hígado/patología , Naftiridinas/toxicidad , Factor de Necrosis Tumoral alfa/farmacología , Animales , Antiinfecciosos/toxicidad , Citocinas/sangre , Fluoroquinolonas/antagonistas & inhibidores , Lipopolisacáridos/antagonistas & inhibidores , Hígado/efectos de los fármacos , Hígado/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Naftiridinas/antagonistas & inhibidores , Neutrófilos/efectos de los fármacos , Neutrófilos/fisiología , Receptores CCR2/sangre , Receptores Tipo I de Factores de Necrosis Tumoral/deficiencia , Receptores Tipo I de Factores de Necrosis Tumoral/fisiología , Receptores Tipo II del Factor de Necrosis Tumoral/deficiencia , Receptores Tipo II del Factor de Necrosis Tumoral/fisiología , Receptores Señuelo del Factor de Necrosis Tumoral/deficiencia , Receptores Señuelo del Factor de Necrosis Tumoral/fisiología , Factor de Necrosis Tumoral alfa/deficiencia , Factor de Necrosis Tumoral alfa/genética , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
OBJECTIVES: The importance of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL receptor expression in pancreatic carcinoma development is not known. To reveal the putative connection of TRAIL and TRAIL receptor expression profile to this process, we analyzed and compared the expression profile of TRAIL and its receptors in pancreatic tissues of both noncancer patients and patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Thirty-one noncancer patients and 34 PDAC patients were included in the study. TRAIL and TRAIL receptor expression profiles were determined by immunohistochemistry. Annexin V binding revealed the apoptotic index in pancreas. Lastly, the tumor grade, tumor stage, tumor diameter, perineural invasion, and number of lymph node metastasis were used for comparison purposes. RESULTS: TRAIL decoy receptor 2 (DcR2) and death receptor 4 expression were up-regulated in PDAC patients compared with noncancer patients, and the ductal cells of PDAC patients displayed significant levels of apoptosis. In addition, acinar cells from PDAC patients had higher DcR2 expression but lower death receptor 4 expression. Increased DcR2 expression was also observed in Langerhans islets of PDAC patients. CONCLUSIONS: Differential alteration of TRAIL and TRAIL receptor expression profiles in PDAC patients suggest that the TRAIL/TRAIL receptor system may play a pivotal role during pancreatic carcinoma development.
Asunto(s)
Adenocarcinoma/patología , Apoptosis , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/patología , Receptores del Factor de Necrosis Tumoral/fisiología , Receptores Señuelo del Factor de Necrosis Tumoral/fisiología , Adenocarcinoma/química , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Ductal Pancreático/química , Niño , Preescolar , Humanos , Lactante , Islotes Pancreáticos/química , Persona de Mediana Edad , Neoplasias Pancreáticas/química , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF , Receptores del Factor de Necrosis Tumoral/análisis , Receptores Señuelo del Factor de Necrosis Tumoral/análisisRESUMEN
Tryptophol is a natural component isolated from vinegar produced from the boiled extract of black soybean. We have reported that tryptophol induces apoptosis in U937 cells via activation of caspase-8 followed by caspase-3. Tryptophol, however, did not affect human peripheral blood lymphocytes (PBL). In this study, we found that tryptophol enhances formation of a death-inducing signaling complex including death receptor (DR) 5. Cell viability and induction of apoptosis by tryptophol was reduced by transfection with decoy receptor (DcR) 1. These results indicate that tryptophol induces apoptosis through DR5 and that the resistance of PBL to tryptophol-induced apoptosis might be due to competition from DcR1.
Asunto(s)
Apoptosis/efectos de los fármacos , Indoles/farmacología , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/fisiología , Caspasa 3/metabolismo , Caspasa 8/metabolismo , Proteínas Ligadas a GPI , Humanos , Linfocitos/efectos de los fármacos , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/efectos de los fármacos , Miembro 10c de Receptores del Factor de Necrosis Tumoral , Receptores Señuelo del Factor de Necrosis Tumoral/fisiología , Células U937RESUMEN
The number and activity of osteoclasts (OCs) are critical for maintaining normal bone turnover. The number is determined by the rates of cell differentiation and death. TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis by interacting with its death receptors, (DR4, DR5). However, its activity can be modulated by two decoy receptors, (DcR1 and DcR2). In this paper we show that TRAIL treatment causes reduced OC viability as well as an increased apoptotic OC number. Loss of nuclei integrity and derangement of the actin microfilament were also induced by TRAIL in OCs. Moreover, we demonstrated the expression of all TRAIL receptors in both precursors and differentiated OCs, and the upregulation of DR5 during OC differentiation. Interestingly, DcR2 was upregulated in the early stage of osteoclastogenesis and downregulated at the end of the differentiation process. We showed that DR5, upregulated by TRAIL, could be the mediator of TRAIL-induced OC apoptosis, since the addition of anti-DR5 neutralizing antibodies restores the OC viability previously reduced by TRAIL. Furthermore, the intracellular pathway induced by TRAIL in OCs involves caspase-8 and Bid activation. In conclusion, our data highlight an important role for the TRAIL/TRAIL receptor system in the regulation of OC apoptosis.
Asunto(s)
Apoptosis/fisiología , Osteoclastos/fisiología , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/fisiología , Ligando Inductor de Apoptosis Relacionado con TNF/fisiología , Apoptosis/efectos de los fármacos , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/fisiología , Caspasa 8/metabolismo , Diferenciación Celular/fisiología , Activación Enzimática , Proteínas Ligadas a GPI , Humanos , Miembro 10c de Receptores del Factor de Necrosis Tumoral , Receptores Señuelo del Factor de Necrosis Tumoral/fisiología , Regulación hacia ArribaRESUMEN
BACKGROUND: In depressed patients, alterations in the hypothalamo-pituitary-adrenocortical (HPA) system are the most consistent neurobiological finding. HPA axis activity and cytokines are intrinsically intertwined: inflammatory cytokines stimulate adrenocorticotropic hormone (ACTH) and cortisol secretion, while, in turn, glucocorticoids suppress the synthesis of proinflammatory cytokines. METHODS: We examined alterations in plasma levels of tumor necrosis factor-alpha (TNF-alpha), levels of its soluble receptors p55 (sTNF-R p55) and p75 (sTNF-R p75) as well as changes in the HPA system function using the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) test on admission and at discharge in 70 depressed inpatients without inflammation. RESULTS: On admission, TNF-alpha levels were inversely associated with the ACTH response to the combined dex/CRH test. Changes in TNF-alpha, sTNF-R p55, and sTNF-R p75 plasma levels from admission to discharge were positively correlated with the dex/CRH test outcome at discharge. Subgroup analysis revealed that this association was restricted to those patients achieving remission. In this subgroup, TNF-alpha levels at discharge were also positively correlated with dex/CRH test response at discharge. CONCLUSIONS: Our results suggest that elevated HPA axis activity in acute depression suppresses TNF-alpha system activity, while after remission, when HPA axis activity has normalized, the TNF-alpha system seems to gain influence on the HPA system.
Asunto(s)
Antidepresivos/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/fisiopatología , Sistema Hipotálamo-Hipofisario/fisiología , Factor de Necrosis Tumoral alfa/fisiología , Adulto , Peso Corporal/efectos de los fármacos , Hormona Liberadora de Corticotropina , Trastorno Depresivo/sangre , Dexametasona , Femenino , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Receptores Tipo I de Factores de Necrosis Tumoral/fisiología , Receptores Tipo II del Factor de Necrosis Tumoral/sangre , Recurrencia , Receptores Señuelo del Factor de Necrosis Tumoral/fisiología , Factor de Necrosis Tumoral alfa/sangreRESUMEN
BACKGROUND AND OBJECTIVES: The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as a potential anticancer agent. However, many cancer cells are resistant to apoptosis induction by TRAIL. The present study was designed to evaluate the sensitivity to TRAIL-induced apoptosis in acute myeloblastic leukemias (AML). DESIGN AND METHODS: TRAIL/TRAIL receptor (TRAIL-R) expression and sensitivity to TRAIL-mediated apoptosis were explored in 79 AML patients, including 17 patients with acute promyelocytic leukemia (APL). RESULTS: In non-APL AML we observed frequent expression of TRAIL decoy receptors (TRAIL-R3 and TRAIL-R4), while TRAIL-R1 and TRAIL-R2 expression was restricted to AML exhibiting monocytic features. Total leukemic blasts, as well as AML colony-forming units (AML-CFU), were invariably resistant to TRAIL-mediated apoptosis. APL express membrane-bound TRAIL on their surface and exhibit a pattern of TRAIL-R expression similar to that observed in the other types of AML. Before, during and after retinoic acid treatment APL cells are TRAIL-resistant. The induction of granulocytic maturation of APL cells by retinoic acid was associated with a marked decline of TRAIL expression. INTERPRETATION AND CONCLUSIONS: The analysis of experimental APL models (i.e., U937 cells engineered to express PML/RAR-Eo and NB4 cells) provided evidence that PML/RAR-Eo expression was associated with downmodulation of TRAIL-R1 and with resistance to TRAIL-mediated apoptosis. We suggest that AML blasts, including APL blasts, are resistant to TRAIL-mediated apoptosis, a phenomenon seemingly related to the expression of TRAIL decoy receptors on these cells. Finally, APL blasts express membrane-bound TRAIL that could confer an immunologic privilege to these cells.