RESUMEN

Tauroursodeoxycholic acid (TUDCA) is a naturally occurring hydrophilic bile acid that alleviates endoplasmic reticulum (ER) stress and inhibits apoptosis, thereby protecting cells. Previous studies have shown that enterovirus 71 (EV71) infection modulates ER stress and induces autophagy to assist viral replication. This study observed the effects of TUDCA pretreatment on HeLa and Vero cells infected with EV71, finding that TUDCA inhibits EV71 replication in TUDCA pretreated HeLa and Vero cells in a dose-dependent manner. We found that TUDCA pretreatment inhibited EV71 replication by regulating three branches of UPR, that is up-regulated ATF6, down-regulated both PERK and IRE1. The results also indicated that autophagy which is downstream of UPR, was inhibited either. The results indicate that TUDCA inhibits EV71 replication by regulating UPR sensor proteins and autophagy following ER stress.

RESUMEN

Innate immune responses (IIR) of the epithelium play a critical role in the initiation and progression of asthma. The core of the IIR is an intracellular signaling pathway activated by pattern recognition receptors (PRRs) to limit the spread of infectious organisms. This chapter will focus on the epithelium as the major innate sentinel cell and its role in acute exacerbations (AEs). Although the pathways of how the IIR activates the NFκB transcription factor, triggering cytokine secretion, dendritic cell activation, and Th2 polarization are well-described, recent exciting work has developed mechanistic insights into how chronic activation of the IIR is linked to mucosal adaptive responses. These adaptations include changes in cell state, now called epithelial-mesenchymal plasticity (EMP). EMP is a coordinated, genomic response to airway injury disrupting epithelial barrier function, expanding the basal lamina, and producing airway remodeling. EMP is driven by activation of the unfolded protein response (UPR), a transcriptional response producing metabolic shunting of glucose through the hexosamine biosynthetic pathway (HBP) to protein N-glycosylation. NFκB signaling and UPR activation pathways potentiate each other in remodeling the basement membrane. Understanding of injury-repair process of epithelium provides new therapeutic targets for precision approaches to the treatment of asthma exacerbations and their sequelae.

Asunto(s)

Asma , Inflamación , Humanos , Inflamación/metabolismo , Inmunidad Innata , FN-kappa B/metabolismo , Transducción de Señal

RESUMEN

The investigation of a phenomenon called the unfolded protein response (UPR) started approximately three decades ago, and we now know that the UPR is involved in a number of cellular events among metazoans, higher plants, and algae. The relevance of the UPR in human diseases featuring protein folding defects, such as Alzheimer's and Huntington's diseases, has drawn much attention to the response in medical research to date. While metazoans and plants share similar molecular mechanisms of the UPR, recent studies shed light on the uniqueness of the plant UPR, with plant-specific protein families appearing to play pivotal roles. Given the considerable emphasis on the original discoveries of key factors in metazoans, this review highlights the uniqueness of the plant UPR based on current knowledge.

Asunto(s)

Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Estrés del Retículo Endoplásmico/fisiología , Plantas/metabolismo , Respuesta de Proteína Desplegada

RESUMEN

Although the functional parameters of microRNAs (miRNAs) have been explored to some extent, the roles of these molecules in coronavirus infection and the regulatory mechanism of miRNAs in virus infection are still unclear. Transmissible gastroenteritis virus (TGEV) is an enteropathgenic coronavirus and causes high morbidity and mortality in suckling piglets. Here, we demonstrated that microRNA-27b-3p (miR-27b-3p) suppressed TGEV replication by directly targeting porcine suppressor of cytokine signaling 6 (SOCS6), while TGEV infection downregulated miR-27b-3p expression in swine testicular (ST) cells and in piglets. Mechanistically, the decrease of miR-27b-3p expression during TGEV infection was mediated by the activated inositol-requiring enzyme 1 (IRE1) pathway of the endoplasmic reticulum (ER) stress. Further studies showed that when ER stress was induced by TGEV, IRE1 acted as an RNase activated by autophosphorylation and unconventionally spliced mRNA encoding a potent transcription factor, X-box-binding protein 1 (Xbp1s). Xbp1s inhibited the transcription of miR-27 and ultimately reduced the production of miR-27b-3p. Therefore, our findings indicate that TGEV inhibits the expression of an anti-coronavirus microRNA through the IRE1 pathway and suggest a novel way in which coronavirus regulates the host cell response to infection.

Asunto(s)

Infecciones por Coronavirus , Coronavirus , MicroARNs , Virus de la Gastroenteritis Transmisible , Animales , Antivirales , Línea Celular , Coronavirus/genética , MicroARNs/genética , Proteínas Serina-Treonina Quinasas/genética , Porcinos , Virus de la Gastroenteritis Transmisible/genética

RESUMEN

BACKGROUND: Inositol-requiring enzyme 1 (IRE1) plays a critical role in attenuating endoplasmic reticulum (ER) stress associated with renal injury which may also be a factor in diabetic nephropathy (DN). Alcohol dehydrogenase type I (ADH1) activity is prominent in the kidney, ADH1 activity is also reported to exert protective effects against ER stress that are not caused by alcohol consumption. However, the role of IRE1 in DN and the correlation between IRE1 and ADH1 activity remain unclear. METHODS: IRE1α floxed mice (Ire1f/f ) of C57BL/6J background were established and crossbred with Ire1αf/f mice to produce podocyte-specific IRE1α knockout mice. Male db/db mice (C57BLKS/J-leprdb/leprdb mice) were used as a DN model. Male mice were made diabetic by injection of streptozotocin. pLKO.1-based vectors encoding short hairpin RNA (shRNA) specific to the IRE1α gene were transfected into HEK293T cells to knockdown IRE1α in mouse podocytes. ELISA, Masson's staining, and electron microscopy were performed to analyze the development of DN. The ADH1 expression was assayed by qPCR and western blot. RESULTS: We found that IRE activity was increased in the glomeruli of DN mouse models. In contrast, ADH1 expression was decreased in these models and mice with podocyte-specific disruption of IRE1 (PKO mice). PKO mice that were made diabetic using strepto-zotocin exhibited accelerated proteinuria, enhanced glomerular fibrosis, and podocyte cell death. In addition, in cultured podocytes, the knockdown of IRE1 downregulated the ADH1 mRNA expression and induced ER stress, consistent with the result of PKO mice, while its detrimental effects were reversed by ADH1 overexpression. CONCLUSIONS: Activation of IRE1 in podocytes serves to limit the progress of DN. The dependence of kidney ADH1 expression on podocyte IRE1 further suggests that ADH1 activity may play an important role downstream of IRE1 in protecting against DN.

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and one of the leading causes of cancer-associated deaths in the world. It is characterised by dismal response rates to conventional therapies. A major challenge in treatment strategies for PDAC is the presence of a dense stroma that surrounds the tumour cells, shielding them from treatment. This unique tumour microenvironment is fuelled by paracrine signalling between pancreatic cancer cells and supporting stromal cell types including the pancreatic stellate cells (PSC). While our molecular understanding of PDAC is improving, there remains a vital need to develop effective, targeted treatments. The unfolded protein response (UPR) is an elaborate signalling network that governs the cellular response to perturbed protein homeostasis in the endoplasmic reticulum (ER) lumen. There is growing evidence that the UPR is constitutively active in PDAC and may contribute to the disease progression and the acquisition of resistance to therapy. Given the importance of the tumour microenvironment and cytokine signalling in PDAC, and an emerging role for the UPR in shaping the tumour microenvironment and in the regulation of cytokines in other cancer types, this review explores the importance of the UPR in PDAC biology and its potential as a therapeutic target in this disease.

RESUMEN

The endoplasmic reticulum is primarily responsible for protein folding and maturation. However, the organelle is subject to varied stress conditions from time to time, which lead to the activation of a signaling program known as the Unfolded Protein Response (UPR) pathway. This pathway, upon sensing any disturbance in the protein-folding milieu sends signals to the nucleus and cytoplasm in order to restore homeostasis. One of the prime UPR signaling sensors is Inositol-requiring enzyme 1 (IRE1); an ER membrane embedded protein with dual enzyme activities, kinase and endoribonuclease. The ribonuclease activity of IRE1 results in Xbp1 splicing in mammals or Hac1 splicing in yeast. However, IRE1 can switch its substrate specificity to the mRNAs that are co-transnationally transported to the ER, a phenomenon known as Regulated IRE1 Dependent Decay (RIDD). IRE1 is also reported to act as a principal molecule that coordinates with other proteins and signaling pathways, which in turn might be responsible for its regulation. The current review highlights studies on IRE1 explaining the structural features and molecular mechanism behind its ribonuclease outputs. The emphasis is also laid on the molecular effectors, which directly or indirectly interact with IRE1 to either modulate its function or connect it to other pathways. This is important in understanding the functional pleiotropy of IRE1, by which it can switch its activity from pro-survival to pro-apoptotic, thus determining the fate of cells.

Asunto(s)

Endorribonucleasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Respuesta de Proteína Desplegada , Animales , Núcleo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico , Humanos , Pliegue de Proteína , Transducción de Señal , Especificidad por Sustrato , Factores de Transcripción/metabolismo , Proteína 1 de Unión a la X-Box/metabolismo

RESUMEN

Despite advances in cancer therapy, several persistent issues remain. These include cancer recurrence, effective targeting of aggressive or therapy-resistant cancers, and selective treatments for transformed cells. This review evaluates the current findings and highlights the potential of targeting the unfolded protein response to treat cancer. The unfolded protein response, an evolutionarily conserved pathway in all eukaryotes, is initiated in response to misfolded proteins accumulating within the lumen of the endoplasmic reticulum. This pathway is initially cytoprotective, allowing cells to survive stressful events; however, prolonged activation of the unfolded protein response also activates apoptotic responses. This balance is key in successful mammalian immune response and inducing cell death in malignant cells. We discuss how the unfolded protein response affects cancer progression, survival, and immune response to cancer cells. The literature shows that targeting the unfolded protein response as a monotherapy or in combination with chemotherapy or immunotherapies increases the efficacy of these drugs; however, systemic unfolded protein response targeting may yield deleterious effects on immune cell function and should be taken into consideration. The material in this review shows the promise of both approaches, each of which merits further research.

Asunto(s)

Estrés del Retículo Endoplásmico , Neoplasias/patología , Microambiente Tumoral , Respuesta de Proteína Desplegada , Chaperón BiP del Retículo Endoplásmico , Endorribonucleasas/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Neoplasias/inmunología , Neoplasias/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T/metabolismo , eIF-2 Quinasa/metabolismo

RESUMEN

The growing evidence shows that in the early stage of type 2 diabetes mellitus (T2DM) development, when challenged by hyperglycemia and/or insulin resistance, pancreatic islets would produce more insulin to maintain the balance of blood sugar, but at the same time, endoplasmic reticulum (ER) stress will be initiated for the reason of over-compensation, which might be a crucial caused factor of dysfunction and death of pancreatic beta cell. In this study, we showed that high glucose induced a remarkably unfolded protein response (UPR) with the phosphorylation of PERK/eIF2α and IRE1α in INS-1 cells, but geniposide prevented the role of high glucose on the phosphorylation of PERK/eIF2α and IRE1α, respectively. Although inhibition of Txnip expression by siRNA had no significant effect on geniposide-regulating UPR, PERK and IRE1α were associated with geniposide-regulating Txnip degradation and glucose-stimulated insulin secretion (GSIS) in high glucose-cultured INS-1 cells. All these data suggest that geniposide might be an important regulator of ER stress and GSIS, and a promising compound for the treatment of T2DM. SIGNIFICANCE OF THE STUDY: Mounting evidence indicates that endoplasmic reticulum (ER) stress plays an essential role to maintain the normal cellular functions and dysfunction. In this study, we revealed that geniposide might be an important regulator of ER stress and glucose-stimulated insulin secretion in pancreatic beta cells.

Asunto(s)

Glucosa/metabolismo , Secreción de Insulina/efectos de los fármacos , Células Secretoras de Insulina/efectos de los fármacos , Iridoides/farmacología , Respuesta de Proteína Desplegada/fisiología , Animales , Línea Celular , Células Secretoras de Insulina/metabolismo , Ratas

RESUMEN

As an endoplasmic reticulum (ER) stress sensor, inositol-requiring enzyme 1 (IRE1) splices the bZIP60 mRNA, and produces an active bZIP60 transcription factor that regulates genes involved in the unfolded protein response (UPR) during ER stresses. This IRE1-bZIP60 pathway is conserved in plant species and recently implicated in plant-pathogen interaction. However, it is unclear whether this IRE1-bZIP60 pathway is involved in Nicotiana attenuata resistance to necrotic fungal pathogen, Alternaria alternata. In this study, transcriptional levels of chaperone protein genes, including luminal binding protein (BiP), protein disulfide isomerase (PDI), calnexin 1-like (CNX 1-like), and calreticulin (CRT), and genes involved in IRE1-bZIP60 pathway, were all significantly induced in N. attenuata leaves after A. alternata inoculation. Silencing IRE1 or bZIP60 led to N. attenuata plants more susceptible to A. alternata, which were associated with reduced gene expressions of Feruloyl-CoA 6'-hydroxylase 1 (F6'H1), a gene encoding a key enzyme for phytoalexin scopoletin and scopolin biosynthesis. Further, electromobility shift assays (EMSA) indicated that bZIP60 protein of spliced form could directly bind to the promoter region of F6'H1 in vitro. JA signaling pathway is required for N. attenuata resistance to A. alternata. Interestingly, the fungus-elicited transcriptional levels of BiP, PDI, CNX 1-like, CRT, IRE1, and bZIP60(s) were all significantly decreased in JA-deficient or JA-insensitive plants. Meanwhile, those genes were significantly induced by methyl jasmonate (MeJA) when applied exogenously. However, the transcriptional levels of JA-regulated genes allene oxide synthase (AOS) and lipoxygenease 3 (LOX3) were not affected in plants impaired with IRE1-bZIP60 pathway. Thus, it is concluded that IRE1-bZIP60 pathway is required for N. attenuata resistance to A. alternata, and JA signaling pathway plays an important role in the elicitation of chaperone protein genes and IRE1-bZIP60 pathway.

RESUMEN

Endoplasmic reticulum (ER) stress is thought to activate autophagy via unfolded protein response (UPR)-mediated transcriptional up-regulation of autophagy machinery components and modulation of microtubule-associated protein 1 light chain 3 (LC3). The upstream UPR constituents pancreatic EIF2-α kinase (PERK) and inositol-requiring enzyme 1 (IRE1) have been reported to mediate these effects, suggesting that UPR may stimulate autophagy via PERK and IRE1. However, how the UPR and its components affect autophagic activity has not been thoroughly examined. By analyzing the flux of LC3 through the autophagic pathway, as well as the sequestration and degradation of autophagic cargo, we here conclusively show that the classical ER stressor tunicamycin (TM) enhances autophagic activity in mammalian cells. PERK and its downstream factor, activating transcription factor 4 (ATF4), were crucial for this induction, but surprisingly, IRE1 constitutively suppressed autophagic activity. TM-induced autophagy required autophagy-related 13 (ATG13), Unc-51-like autophagy-activating kinases 1/2 (ULK1/ULK2), and GABA type A receptor-associated proteins (GABARAPs), but interestingly, LC3 proteins appeared to be redundant. Strikingly, ATF4 was activated independently of PERK in both LNCaP and HeLa cells, and our further examination revealed that ATF4 and PERK regulated autophagy through separate mechanisms. Specifically, whereas ATF4 controlled transcription and was essential for autophagosome formation, PERK acted in a transcription-independent manner and was required at a post-sequestration step in the autophagic pathway. In conclusion, our results indicate that TM-induced UPR activates functional autophagy, and whereas IRE1 is a negative regulator, PERK and ATF4 are required at distinct steps in the autophagic pathway.

Asunto(s)

Factor de Transcripción Activador 4/metabolismo , Muerte Celular Autofágica/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Tunicamicina/farmacología , Respuesta de Proteína Desplegada/efectos de los fármacos , eIF-2 Quinasa/metabolismo , Factor de Transcripción Activador 4/genética , Muerte Celular Autofágica/genética , Autofagosomas/metabolismo , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Estrés del Retículo Endoplásmico/genética , Endorribonucleasas/genética , Endorribonucleasas/metabolismo , Células HeLa , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Células PC-3 , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transcripción Genética/efectos de los fármacos , Transcripción Genética/genética , Respuesta de Proteína Desplegada/genética , eIF-2 Quinasa/genética

RESUMEN

The endoplasmic reticulum (ER) is a critical organelle for protein synthesis, folding and modification, and lipid synthesis and calcium storage. Dysregulation of ER functions leads to the accumulation of misfolded- or unfolded-protein in the ER lumen, and this triggers the unfolded protein response (UPR), which restores ER homeostasis. The UPR is characterized by three distinct downstream signaling pathways that promote cell survival or apoptosis depending on the stressor, the intensity and duration of ER stress, and the cell type. Mammalian cells express the UPR transducers IRE1, PERK, and ATF6, which control transcriptional and translational responses to ER stress. Direct links between ER stress and immune responses are also evident, but the mechanisms by which UPR signaling cascades are coordinated with immunity remain unclear. This review discusses recent investigations of the roles of ER stress in immune responses that lead to differentiation, maturation, and cytokine expression in immune cells. Further understanding of how ER stress contributes to the pathogenesis of immune disorders will facilitate the development of novel therapies that target UPR pathways.

Asunto(s)

Estrés del Retículo Endoplásmico/inmunología , Respuesta de Proteína Desplegada/inmunología , Proteína 1 de Unión a la X-Box/inmunología , Diferenciación Celular , Humanos

RESUMEN

The endoplasmic reticulum (ER) is a membranous network with an intricate dynamic architecture necessary for various essential cellular processes. Nearly one third of the proteins trafficking through the secretory pathway are folded and matured in the ER. Additionally, it acts as calcium storage, and it is a main source for lipid biosynthesis. The ER is highly connected with other organelles through regions of membrane apposition that allow organelle remodeling, as well as lipid and calcium traffic. Cells are under constant changes due to metabolic requirements and environmental conditions that challenge the ER network’s maintenance. The unfolded protein response (UPR) is a signaling pathway that restores homeostasis of this intracellular compartment upon ER stress conditions by reducing the load of proteins, and by increasing the processes of protein folding and degradation. Significant progress on the study of the mechanisms that restore ER homeostasis was achieved using model organisms such as yeast, Arabidopsis, and mammalian cells. In this review, we address the current knowledge on ER architecture and ER stress response in Dictyostelium discoideum. This social amoeba alternates between unicellular and multicellular phases and is recognized as a valuable biomedical model organism and an alternative to yeast, particularly for the presence of traits conserved in animal cells that were lost in fungi.

RESUMEN

Brucella spp. are intracellular vacuolar pathogens that causes brucellosis, a worldwide zoonosis of profound importance. We previously demonstrated that the activity of host unfolded protein response (UPR) sensor IRE1α (inositol-requiring enzyme 1) and ER-associated autophagy confer susceptibility to Brucella melitensis and Brucella abortus intracellular replication. However, the mechanism by which host IRE1α regulates the pathogen intracellular lifestyle remains elusive. In this study, by employing a diverse array of molecular approaches, including biochemical analyses, fluorescence microscopy imaging, and infection assays using primary cells derived from Ern1 (encoding IRE1) conditional knockout mice, we address this gap in our understanding by demonstrating that a novel IRE1α to ULK1, an important component for autophagy initiation, signaling axis confers susceptibility to Brucella intracellular parasitism. Importantly, deletion or inactivation of key signaling components along this axis, including IRE1α, BAK/BAX, ASK1, and JNK as well as components of the host autophagy system ULK1, Atg9a, and Beclin 1, resulted in striking disruption of Brucella intracellular trafficking and replication. Host kinases in the IRE1α-ULK1 axis, including IRE1α, ASK1, JNK1, and/or AMPKα as well as ULK1, were also coordinately phosphorylated in an IRE1α-dependent fashion upon the pathogen infection. Taken together, our findings demonstrate that the IRE1α-ULK1 signaling axis is subverted by the bacterium to promote intracellular parasitism, and provide new insight into our understanding of the molecular mechanisms of intracellular lifestyle of Brucella.

Asunto(s)

Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Brucella melitensis/patogenicidad , Brucelosis/patología , Endorribonucleasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Autofagia/fisiología , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/genética , Beclina-1/genética , Brucelosis/microbiología , Línea Celular , Drosophila melanogaster , Endorribonucleasas/genética , Interacciones Huésped-Patógeno/fisiología , Proteínas Quinasas JNK Activadas por Mitógenos/genética , MAP Quinasa Quinasa Quinasa 5/genética , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Células RAW 264.7 , Transducción de Señal/fisiología , Respuesta de Proteína Desplegada/fisiología , Proteínas de Transporte Vesicular/genética , Proteína Destructora del Antagonista Homólogo bcl-2/genética , Proteína X Asociada a bcl-2/genética

RESUMEN

In response to the endoplasmic reticulum (ER) stress induced by herpes simplex virus type 1 (HSV-1) infection, host cells activate the unfolded protein response (UPR) to reduce the protein-folding burden in the ER. The regulation of UPR upon HSV-1 infection is complex, and the downstream effectors can be detrimental to viral replication. Therefore, HSV-1 copes with the UPR to create a beneficial environment for its replication. UPR has three branches, including protein kinase RNA (PKR)-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activated transcription factor 6 (ATF6). IRE1α is the most conserved branch of UPR which has both RNase and kinase activities. Previous studies have shown that IRE1α RNase activity was inactivated during HSV-1 infection. However, the effect of the two activities of IRE1α on HSV-1 replication remains unknown. Results in this study showed that IRE1α expression was up-regulated during HSV-1 infection. We found that in HEC-1-A cells, increasing RNase activity, or inhibiting kinase activity of IRE1α led to viral suppression, indicating that the kinase activity of IRE1α was beneficial, while the RNase activity was detrimental to viral replication. Further evidence showed that the kinase activity of IRE1α leads to the activation of the JNK (c-Jun N-terminal kinases) pathway, which enhances viral replication. Taken together, our evidence suggests that IRE1α is involved in HSV-1 replication, and its RNase and kinase activities play differential roles during viral infection.

Asunto(s)

Endorribonucleasas/metabolismo , Endorribonucleasas/farmacología , Herpesvirus Humano 1/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/farmacología , Ribonucleasas/metabolismo , Replicación Viral/efectos de los fármacos , Proteína 1 de Unión a la X-Box/farmacología , Animales , Antivirales/farmacología , Línea Celular , Chlorocebus aethiops , Replicación del ADN , Estrés del Retículo Endoplásmico , Endorribonucleasas/farmacocinética , Regulación de la Expresión Génica , Células HeLa , Herpes Simple/metabolismo , Herpes Simple/virología , Herpesvirus Humano 1/metabolismo , Herpesvirus Humano 1/patogenicidad , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fosforilación/fisiología , Proteínas Serina-Treonina Quinasas/farmacocinética , Empalme del ARN , ARN Mensajero/metabolismo , ARN Interferente Pequeño/análisis , Transducción de Señal/genética , Respuesta de Proteína Desplegada , Regulación hacia Arriba , Células Vero , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismo

RESUMEN

OBJECTIVE: Recent reports have shown that endoplasmic reticulum stress is associated with cancer. However, the impacts of endoplasmic reticulum stress on the prognosis of lung cancer are unknown. Therefore, in this study, we sought to reveal the relationship between the expression of endoplasmic reticulum stress-related genes (endoplasmic reticulum oxidoreductase 1L, protein kinase RNA-like endoplasmic reticulum kinase, activating transcription factor 6 and inositol-requiring kinase 1) and the outcome of lung adenocarcinoma. METHODS: One hundred and twenty-six patients with surgically resected lung adenocarcinomas were subjected to an endoplasmic reticulum stress-related mRNA expression analysis using quantitative RT-PCR. The following parameters were analyzed for all the study patients: age, sex, disease stage, smoking status, lymph node invasion (ly), vascular invasion (v) and EGFR mutation status. We assigned patients to either a high-expression group or a low-expression group according to the expression levels of endoplasmic reticulum stress-related genes. RESULTS: High expressions of endoplasmic reticulum stress-related genes were observed in patients with lower stages of lung adenocarcinoma and minimal vascular invasion. A Kaplan-Meier analysis showed significant differences in recurrence-free survival and overall survival between high-expression group and low-expression group. High inositol-requiring kinase 1 expression was an independent predictor of recurrence-free survival among patients with lung adenocarcinoma (hazard ratio, 0.396; 95% confidence interval, 0.188-0.834; P = 0.015). CONCLUSIONS: Inositol-requiring kinase 1 may be a useful biomarker to predict recurrence in surgically resected lung adenocarcinoma patients.

Asunto(s)

Adenocarcinoma/genética , Adenocarcinoma/patología , Endorribonucleasas/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Recurrencia Local de Neoplasia/patología , Proteínas Serina-Treonina Quinasas/genética , Adenocarcinoma/irrigación sanguínea , Adenocarcinoma del Pulmón , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Estrés del Retículo Endoplásmico/genética , Endorribonucleasas/metabolismo , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/irrigación sanguínea , Masculino , Persona de Mediana Edad , Análisis Multivariante , Mutación , Neovascularización Patológica/genética , Pronóstico , Modelos de Riesgos Proporcionales , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo

RESUMEN

4-hydroxynonenal (HNE) is a lipid hydroperoxide end product formed from the oxidation of n-6 polyunsaturated fatty acids. The relative abundance of HNE within the vasculature is dependent not only on the rate of lipid peroxidation and HNE synthesis but also on the removal of HNE adducts by phase II metabolic pathways such as glutathione-S-transferases. Depending on its relative concentration, HNE can induce a range of hormetic effects in vascular endothelial and smooth muscle cells, including kinase activation, proliferation, induction of phase II enzymes and in high doses inactivation of enzymatic processes and apoptosis. HNE also plays an important role in the pathogenesis of vascular diseases such as atherosclerosis, diabetes, neurodegenerative disorders and in utero diseases such as pre-eclampsia. This review examines the known production, metabolism and consequences of HNE synthesis within vascular endothelial and smooth muscle cells, highlighting alterations in mitochondrial and endoplasmic reticulum function and their association with various vascular pathologies.

Asunto(s)

Aldehídos/metabolismo , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Salud , Músculo Liso/metabolismo , Músculo Liso/patología , Transducción de Señal , Retículo Endoplásmico/metabolismo , Endotelio Vascular/citología , Humanos , Mitocondrias/metabolismo , Músculo Liso/citología , Oxidación-Reducción