RESUMEN
Vascular restenosis often presents as a consequence of injury to the vessel wall, resulting from stenting and other interventional procedures. Such injury to the arteries induces proliferation of Vascular Smooth Muscle Cells (VSMCs), resulting in cellular hyperplasia and restenosis. We and others have previously reported de-novo production of different cytokines and growth factors such as Tumor Necrosis Factor Alpha (TNF-α) and Insulin like Growth Factor 1 (IGF-1), after vascular injury. As complex as it is, the profuse proliferation of VSMCs appears to be occurring due to several induced factors which initiate molecular mechanisms and exacerbate disease conditions. In many pathological events, the deleterious effects of TNF-α and IGF-1 in initiating disease mechanisms was reported. In the present work, we explored whether TNF-α and IGF-1 can regulate epigenetic mechanisms that promote proliferation of VSMCs. We investigated the mechanistic roles of proteins which can structurally interact with DNMT1 and initiate cellular pathways that promote proliferation of VSMCs. Our findings here, identify a novel molecular mechanism that is initiated by TNF-α and IGF-1. It was previously reported that DNMT1 expression is directly induced by TNF-α and IGF-1 treatment and increased/induced expression of DNMT1 causes silencing of genes that are essential to maintaining cellular homeostasis such as the tumor suppressor genes. We have earlier reported that TNF-α and IGF-1 treatment elevates DNMT1 expression in VSMCs and causes increased VSMC proliferation. However, the molecular mechanisms involved were not fully deciphered. Interestingly, in the present study we found that TNF-α and IGF-1 treatment failed to elevate DNMT1 expression levels in absence of HDAC2 and HDAC10. Also, while HDAC2 expression was not affected by HDAC10 knockdown, HDAC2 is essentially required for HDAC10 expression. Further, in TNF-α and IGF-1 induced epigenetic signaling mechanism, the expression of two important proteins EZH2 and PCNA seem to be regulated in an HDAC2-HDAC10 dependent manner. Our results show an inter-dependence of epigenetic mediators in inducing proliferation in VSMCs. To our knowledge, this is the first report that shows HDAC2 dependent expression of HDAC10, and suggests a novel mechanistic link between DNMT1, HDAC10 and HDAC2 that regulates EZH2 and PCNA to enhance cell proliferation of VSMCs which is the underlying cause for neointimal hyperplasia and restenosis.
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Factor de Necrosis Tumoral alfaRESUMEN
Introduction: A multitude of cellular and physiological functions have been attributed to the biological activity of PTEN (Phosphatase and tensin homolog) such as inhibiting angiogenesis, promoting apoptosis, preventing cell proliferation, and maintaining cellular homeostasis. Based on whether cell growth is needed to be initiated or to be inhibited, enhancing PTEN expression or seeking to inhibit it was pursued. Areas covered: Here the authors provide recent updates to their previous publication on 'PTEN modulators: A patent review', and discuss on new specificities that affirm the therapeutic potential of PTEN in promoting neuro-regeneration, stem cell regeneration, autophagy, bone and cartilage regeneration. Also, targeting PTEN appears to be effective in developing new treatment strategies for Parkinson's disease, Alzheimer's disease, macular degeneration, immune disorders, asthma, arthritis, lupus, Crohn's disease, and several cancer types. Expert opinion: PTEN mainly inhibits the PI3k/Akt pathway. However, the PI3k/Akt pathway can be activated by other signaling proteins. Thus, novel treatment strategies that can regulate PTEN alone, or combinational treatment approaches that can induce PTEN and simultaneously affect downstream mediators in the PI3K/Akt pathway, are needed, which were not investigated in detail. Commercial interests associated with molecules that regulate PTEN are discussed here, along with limitations and new possibilities to improve them.
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Desarrollo de Medicamentos/métodos , Fosfohidrolasa PTEN/efectos de los fármacos , Animales , Humanos , Fosfohidrolasa PTEN/metabolismo , Patentes como Asunto , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Cellular inflammation is not just an immediate response following pathogenic infections or resulting from damage due to injury, it is also associated with normal physiological functions, including wound healing and tissue repair. The existence of such a definitive role in normal physiology and in disease pathology indicates the presence of a regulatory mechanism that is tightly controlled in normal cells. A tight control over gene expression is associated with regulatory mechanisms in the cells, which can be either inducible or epigenetic. Among other intracellular mechanisms that contribute to epigenetic gene regulation, DNA methylation has been shown to maintain a tight control over gene expression through the actions of DNA methyltransferases (DNMTs). With a clear role in developmental and tissuespecific temporal gene regulation, the involvement of DNMTs is evident in normal and pathological conditions. In this review article, inflammation in tendons associated with disease pathology and tissue repair or regeneration at the musculoskeletal joints is critically reviewed. More specifically, the review focuses on known epigenetic mechanisms and their role in the clinical presentation of the disease in human joint disorders associated with tendon inflammation, with an emphasis on the gene regulatory mechanisms that are controlled through DNA methylation, histone deacetylation, and microRNAs.
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Epigénesis Genética , Inflamación/genética , Tendones/patología , Animales , ADN/genética , Metilación de ADN , Histonas/metabolismo , HumanosRESUMEN
Fatty infiltration and inflammation delay the healing responses and raise major concerns in the therapeutic management of rotator cuff tendon injuries (RCTI). Our evaluations showed the upregulation of 'metabolic check point' AMPK and inflammatory molecule, TREM-1 from shoulder biceps tendons collected from RCTI subjects. However, the epigenetic regulation of these biomolecules by miRNAs is largely unknown and it is likely that a deeper understanding of the mechanism of action can have therapeutic potential for RCTI. Based on this background, we have evaluated the miRNAs from RCTI patients with fatty infiltration and inflammation (FI group) and compared with RCTI patients without fatty infiltration and inflammation (No-FI group). NetworkAnalyst was employed to evaluate the genes interconnecting AMPK and TREM-1 pathway, using PRKAA1 (AMPK), TREM-1, HIF1α, HMGB1, and AGER as input genes. The most relevant miRNAs were screened by considering the fold change below - 7.5 and the number of target genes 10 and more which showed 13 miRNAs and 216 target genes. The exact role of these miRNAs in the fatty infiltration and inflammation associated with RCTI is still unknown and the understanding of biological activity of these miRNAs can pave ways to develop miRNA-based therapeutics in the management of RCTI.
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Inflamación , MicroARNs/metabolismo , Manguito de los Rotadores/metabolismo , Transducción de Señal , Traumatismos de los Tendones/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , MicroARNs/genética , Manguito de los Rotadores/patología , Traumatismos de los Tendones/patología , Receptor Activador Expresado en Células Mieloides 1/metabolismoRESUMEN
Vitamin D functions as a potent immunomodulator by interacting with many immune cells however, its role in regulating inflammation in the epicardial adipose tissue (EAT) is unclear. In the EAT of atherosclerotic microswine that were fed with deficient, sufficient or supplemented levels of vitamin D, we evaluated the phenotype of the macrophages. Vitamin D treatment was continued for 12 months and serum 25(OH)D levels were measured regularly. Infiltration of M1/M2 macrophage was investigated by immunostaining for CCR7 and CD206, respectively in conjunction with a pan macrophage marker CD14. Significant difference in the number of CCR7+ cells was observed in the EAT from vitamin D-deficient swine compared to vitamin D-sufficient or -supplemented swine. Expression of CD206 correlated with high levels of serum 25(OH)D indicating a significant increase in M2 macrophages in the EAT of vitamin D-supplemented compared to -deficient swine. These findings suggest that vitamin D-deficiency exacerbates inflammation by increasing pro-inflammatory M1 macrophages, while vitamin D-supplementation attenuates the inflammatory cytokines and promotes M2 macrophages in EAT. This study demonstrates the significance of vitamin D mediated inhibition of macrophage mediated inflammation in the EAT during coronary intervention in addition to its immunomodulatory role. However, additional studies are required to identify the cellular mechanisms that transduce signals between macrophages and smooth muscle cells during restenosis in the presence and absence of vitamin D.
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Tejido Adiposo/metabolismo , Aterosclerosis/metabolismo , Macrófagos/metabolismo , Pericardio/metabolismo , Vitamina D/sangre , Animales , Enfermedad de la Arteria Coronaria/genética , Reestenosis Coronaria , Suplementos Dietéticos , Femenino , Inflamación , Fenotipo , Receptores de Calcitriol/genética , Porcinos , Deficiencia de Vitamina D/sangre , Vitaminas/sangreRESUMEN
Increased expression of DNA methyltransferase-1 (DNMT1) associates with the progression of many human diseases. Because DNMT1 induces cell proliferation, drugs that inhibit DNMT1 have been used to treat proliferative diseases. Because these drugs are nonspecific inhibitors of DNMT1, subsidiary events or the compensatory mechanisms that are activated in the absence of DNMT1 limit their therapeutic application. Here, we studied the molecular mechanisms that occur during angioplasty-induced restenosis and found that DNMT1 inhibition in both in vitro and in vivo approaches resulted in the induction of DNA methyltransferase-3a (DNMT3a) expression. In vascular smooth muscle cells (VSMCs), the microRNA hsa-miR-1264 mimic, specifically inhibiting DNMT1, induced nuclear expression of DNMT3a. On the contrary, there was no induced expression of DNMT3a in VSMCs that were transfected with hsa-miR-1264 inhibitor. Further, ectopic expression of suppressor of cytokine signaling 3 (SOCS3) through adeno-associated virus (AAV)-mediated gene delivery in the coronary arteries of Yucatan microswine showed inhibition of both DNMT1 and DNMT3a in vivo. These findings show the existence of an inter-regulatory mechanism between DNMT1 and DNMT3a where, in the absence of DNMT1, induction of DNMT3a compensates for the loss of DNMT1 functions, suggesting that the inhibition of both DNMT1 and DNMT3a are required to prevent restenosis.
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Angioplastia/efectos adversos , Reestenosis Coronaria/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/antagonistas & inhibidores , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Inhibidores Enzimáticos/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Reestenosis Coronaria/etiología , Reestenosis Coronaria/genética , ADN Metiltransferasa 3A , HumanosRESUMEN
Histone modifications are the key epigenetic mechanisms that have been identified to regulate gene expression in many human diseases. However, in the early developmental stages, such as in utero and the postnatal stages, histone modifications are essential for gene regulation and cell growth. Atherosclerosis represents a classical example of the involvement of different cell types, and their cumulative effects in the development of atheroma and the progression of the disease. Post translational modifications on proteins either induces their functional activity or renders them inactive. Post translational modifications such as methylation or acetylation on histones have been well characterized, and their role in enhancing or inhibiting specific gene expression was clearly elucidated. In the present review article, the critical roles of different histone modifications that occur in atherosclerosis have been summarized. Different histone proteins have been identified to serve a critical role in the development of atherosclerosis. Specifically, histone methylation and histone acetylation in monocytes, macrophages, vascular smooth muscle cells and in endothelial cells during the progression of atherosclerosis, have been well reported. In recent years, different target molecules and genes that regulate histone modifications have been examined for their effects in the treatment of atherosclerosis in animal models and in clinical trials. An increasing body of evidence suggests that these epigenetic changes resulting from DNA methylation and noncoding RNA may also be associated with histone modifications, thereby indicating that novel therapeutic strategies can be developed by targeting these post translational modifications, which may in turn aid in the treatment of atherosclerosis.
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Aterosclerosis/metabolismo , Histonas/metabolismo , Placa Aterosclerótica/metabolismo , Procesamiento Proteico-Postraduccional , Acetilación , Animales , Aterosclerosis/patología , Aterosclerosis/terapia , Modelos Animales de Enfermedad , Humanos , Metilación , Placa Aterosclerótica/patología , Placa Aterosclerótica/terapiaRESUMEN
Inflammation is associated with glenohumeral arthritis and rotator cuff tendon tears. Epigenetically, miRNAs tightly regulate various genes involved in the inflammatory response. Alterations in the expression profile of miRNAs and the elucidation of their target genes with respect to the pathophysiology could improve the understanding of their regulatory role and therapeutic potential. Here, we screened key miRNAs that mediate inflammation and linked with JAK2/STAT3 pathway with respect to the coincidence of glenohumeral arthritis in patients suffering from rotator cuff injury (RCI). Human resected long head of the biceps tendons were examined for miRNA profile from two groups of patients: Group 1 included the patients with glenohumeral arthritis and massive rotator cuff tears and the Group 2 patients did not have arthritis or rotator cuff tears. The miRNA profiling revealed that 235 miRNAs were highly altered (fold change less than -3 and greater than +2 were considered). Data from the NetworkAnalyst program revealed the involvement and interaction between 3,430 different genes associated with inflammation out of which 284 genes were associated with JAK2/STAT3 pathway and interconnect 120 different pathways of inflammation. Around 1,500 miRNAs were found to play regulatory role associated with these genes of inflammatory responses and 77 miRNAs were found to regulate more than 10 genes. Among them, 25 genes with less than tenfold change were taken to consideration which altogether constitute for the regulation of 102 genes. Targeting these miRNAs and the underlying regulatory mechanisms may advance our knowledge to develop promising therapies in the management of shoulder tendon pathology.
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Artritis/metabolismo , Tendinopatía del Codo/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , MicroARNs/biosíntesis , Articulación del Hombro/metabolismo , Artritis/patología , Tendinopatía del Codo/patología , Femenino , Humanos , Inflamación/metabolismo , Inflamación/patología , Masculino , Articulación del Hombro/patologíaAsunto(s)
Fibrilación Atrial , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Canal de Potasio ERG1 , Electrocardiografía/métodos , Terapia Genética/métodos , Sistema de Conducción Cardíaco , Complicaciones Posoperatorias , Potenciales de Acción/efectos de los fármacos , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/etiología , Fibrilación Atrial/metabolismo , Fibrilación Atrial/prevención & control , Canal de Potasio ERG1/antagonistas & inhibidores , Canal de Potasio ERG1/metabolismo , Sistema de Conducción Cardíaco/efectos de los fármacos , Sistema de Conducción Cardíaco/metabolismo , Humanos , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/metabolismo , Complicaciones Posoperatorias/prevención & controlAsunto(s)
Reprogramación Celular , Cardiopatías , Animales , Plumas , Fibroblastos , Miocitos Cardíacos , Regeneración , Medicina RegenerativaRESUMEN
The extracellular matrix (ECM) provides core support which is essential for the cell and tissue architectural development. The role of ECM in many pathological conditions has been well established and ECM-related abnormalities leading to serious consequences have been identified. Though much has been explored in regards to the role of ECM in soft tissue associated pathologies, very little is known about its role in inflammatory disorders in tendon. In this study, we performed microRNA (miRNA) expression analysis in the long head of the human shoulder biceps tendon to identify key genes whose expression was altered during inflammation in patients with glenohumeral arthritis. We identified differential regulation of matrix metalloproteinases (MMPs) that could be critical in collagen type replacement during tendinopathy. The miRNA profiling showed consistent results between the groups and revealed significant changes in the expression of seven different miRNAs in the inflamed tendons. Interestingly, all of these seven miRNAs were previously reported to have either a direct or indirect role in regulating the ECM organization in other pathological disorders. In addition, these miRNAs were also found to alter the expression levels of MMPs, which are the key matrix degrading enzymes associated with ECM-related abnormalities and pathologies. To our knowledge, this is the first report which identifies specific miRNAs associated with inflammation and the matrix reorganization in the tendons. Furthermore, the findings also support the potential role of these miRNAs in altering the collagen type ratio in the tendons during inflammation which is accompanied with differential expression of MMPs.
Asunto(s)
Artritis/genética , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Matriz Extracelular , MicroARNs/genética , Articulación del Hombro/patología , Tendinopatía/genética , Artritis/metabolismo , Artritis/patología , Estudios de Casos y Controles , Colágeno/metabolismo , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Perfilación de la Expresión Génica , Estudios de Asociación Genética , Humanos , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Análisis por Micromatrices , Hombro , Articulación del Hombro/metabolismo , Tendinopatía/metabolismo , Tendinopatía/patología , TendonesRESUMEN
OBJECTIVE: The role of vitamin D deficiency in coronary artery disease (CAD) progression is uncertain. Chronic inflammation in epicardial adipose tissue (EAT) has been implicated in the pathogenesis of CAD. However, the molecular mechanism underlying vitamin D deficiency-enhanced inflammation in the EAT of diseased coronary arteries remains unknown. We examined a mechanistic link between 1,25-dihydroxyvitamin D-mediated suppression of nuclear factor-κB (NF-κB) transporter, karyopherin α4 (KPNA4) expression and NF-κB activation in preadipocytes. Furthermore, we determined whether vitamin D deficiency accelerates CAD progression by increasing KPNA4 and nuclear NF-κB levels in EAT. APPROACH AND RESULTS: Nuclear protein levels were detected by immunofluorescence and Western blot. Exogenous KPNA4 was transported into cells by a transfection approach and constituted lentiviral vector. Swine were administered vitamin D-deficient or vitamin D-sufficient hypercholesterolemic diet. After 1 year, the histopathology of coronary arteries and nuclear protein expression of EAT were assessed. 1,25-dihydroxyvitamin D inhibited NF-κB activation and reduced KPNA4 levels through increased vitamin D receptor expression. Exogenous KPNA4 rescued 1,25-dihydroxyvitamin D-dependent suppression of NF-κB nuclear translocation and activation. Vitamin D deficiency caused extensive CAD progression and advanced atherosclerotic plaques, which are linked to increased KPNA4 and nuclear NF-κB levels in the EAT. CONCLUSIONS: 1,25-dihydroxyvitamin D attenuates NF-κB activation by targeting KPNA4. Vitamin D deficiency accelerates CAD progression at least, in part, through enhanced chronic inflammation of EAT by upregulation of KPNA4, which enhances NF-κB activation. These novel findings provide mechanistic evidence that vitamin D supplementation could be beneficial for the prevention and treatment of CAD.
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Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Enfermedad de la Arteria Coronaria/etiología , Deficiencia de Vitamina D/complicaciones , Transporte Activo de Núcleo Celular , Adipocitos/efectos de los fármacos , Adipocitos/patología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/patología , Animales , Células Cultivadas , Enfermedad de la Arteria Coronaria/metabolismo , Enfermedad de la Arteria Coronaria/patología , Enfermedad de la Arteria Coronaria/prevención & control , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Hipercolesterolemia/complicaciones , Interferencia de ARN , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Porcinos , Porcinos Enanos , Factores de Tiempo , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , Transfección , Vitamina D/análogos & derivados , Vitamina D/farmacología , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/metabolismo , Deficiencia de Vitamina D/patología , alfa Carioferinas/genética , alfa Carioferinas/metabolismoRESUMEN
The innate immune response, which is usually referred to as the first line of defense, protects the hosts against pathogenic micro-organisms. Some of the biomolecules released from the pathogens, such as proteins, lipoproteins and nucleic acids, which are collectively termed as pathogen-associated molecular patterns (PAMPs), elicit signaling mechanisms that trigger immune responses in the hosts. Pathogen recognition receptors (PRRs) on the host cells recognize these PAMPs and initiate intracellular signaling through toll-like receptors (TLRs), RIG-I-like receptors (RLRs), and other pathways which induce production of pro-inflammatory cytokines and type I interferons. Recently, different members of tripartite motif containing proteins (TRIM) family of proteins were identified to intercept and regulate these cellular pathways. Specific targets of TRIM proteins have been identified and their molecular mechanisms were unraveled and identified unique domains involved in protein-protein interactions. Though innate immunity represents a tight and well conserved immune system in the host, gene expression in innate immunity was identified to be influenced by several epigenetic mechanisms including regulation by microRNAs (miRNAs). In this review, we present critical analysis of the findings on the identification of specific miRNAs that modulate expression of target genes involved in the regulation of innate immunity.
RESUMEN
Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered.
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Heterogeneidad Genética , Terapia Molecular Dirigida , Neoplasias/terapia , Medicina de Precisión , Antineoplásicos Fitogénicos/uso terapéutico , Resistencia a Antineoplásicos/genética , Humanos , Neoplasias/genética , Neoplasias/patología , Neoplasias/prevención & control , Transducción de Señal , Microambiente Tumoral/genéticaRESUMEN
Previously we found decreased expression of SOCS3 in neointimal hyperplastic region following balloon angioplasty in atherosclerotic micro swine. In our recent in vitro studies using human coronary artery smooth muscle cells (HCASMC), we observed the inhibition of SOCS3 expression in the presence of both TNF-α and IGF-1, correlating with the in vivo findings in microswine. We also reported that two independent mechanisms, JAK/STAT3/NFκB and promoter methylation of SOCS3 were responsible for TNF-α and IGF-1 induced SOCS3 inhibition. In this study, using miRNA array and gene expression approaches, we explored the molecular mechanisms involved in the above SOCS3 repression and identified several miRNAs that are associated with the regulation of SOCS3 expression. Our miRNA expression profiling revealed profound down-regulation of two specific miRNAs, hsa-miR-758 and hsa-miR-1264, whose expression levels were decreased by 8-10 folds in HCASMCs that were treated with both TNF-α and IGF-1. This was accompanied with a significant up-regulation of three specific miRNAs, hsa-miR-155, hsa-miR-146b-5p and hsa-miR-146a, which showed about 3-7 fold increases in their expression levels. Importantly, we also found that the miRNA hsa-miR-1264 targets DNA methyltransferase-1 (DNMT1) transcripts by binding to its 3'UTR region to affect its expression. Expression of hsa-miR-1264 in HCASMCs not only resulted in decreased DNMT1 mRNA transcripts but it also increased SOCS3 expression. The treatment with TNF-α and IGF-1 resulted in drastic decrease in hsa-miR-1264 levels with no change in the expression of DNMT1. Consequently, the DNMT1 activity caused hypermethylation in the CpG island of the SOCS3 promoter region and inhibited its expression. This could be a causative epigenetic mechanism associated with TNF-α and IGF-1 induced smooth muscle cell proliferation involved in the pathogenesis of coronary artery hyperplasia and restenosis.
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Vasos Coronarios/metabolismo , ADN (Citosina-5-)-Metiltransferasas/genética , Silenciador del Gen , MicroARNs/fisiología , Miocitos del Músculo Liso/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/genética , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Regulación hacia Abajo , Humanos , Factor I del Crecimiento Similar a la Insulina/fisiología , Transducción de Señal , Proteína 3 Supresora de la Señalización de Citocinas , Transcriptoma , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.
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Antineoplásicos/uso terapéutico , Inflamación/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Transformación Celular Neoplásica/efectos de los fármacos , Heterogeneidad Genética/efectos de los fármacos , Humanos , Inflamación/genética , Inflamación/patología , Terapia Molecular Dirigida , Neoplasias/genética , Neoplasias/patología , Transducción de Señal/efectos de los fármacosRESUMEN
Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer.
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Apoptosis/genética , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Autofagia/genética , Proliferación Celular/genética , Resistencia a Antineoplásicos/genética , Humanos , Neoplasias/patología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persistent cytostasis. This state, termed "senescence," can be triggered by intrinsic cellular processes such as telomere dysfunction and oncogene expression, and by exogenous factors such as DNA damaging agents or oxidative environments. Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised. Doses of conventional genotoxic drugs required to achieve cancer cell senescence are often much lower than doses required to achieve outright cell death. Additional therapies, such as those targeting cyclin dependent kinases or components of the PI3K signaling pathway, may induce senescence specifically in cancer cells by circumventing defects in tumor suppressor pathways or exploiting cancer cells' heightened requirements for telomerase. Such treatments sufficient to induce cancer cell senescence could provide increased patient survival with fewer and less severe side effects than conventional cytotoxic regimens. This positive aspect is countered by important caveats regarding senescence reversibility, genomic instability, and paracrine effects that may increase heterogeneity and adaptive resistance of surviving cancer cells. Nevertheless, agents that effectively disrupt replicative immortality will likely be valuable components of new combinatorial approaches to cancer therapy.
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Proliferación Celular/genética , Senescencia Celular/genética , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Inestabilidad Genómica/efectos de los fármacos , Humanos , Neoplasias/patología , Fosfatidilinositol 3-Quinasas/genética , Transducción de Señal/genética , Telomerasa/efectos de los fármacos , Telomerasa/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology.