RESUMEN
TGF-ß, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to antagonize transcriptional activation by TGF-ß/SMAD. This antagonism involves reduced phosphorylation of SMADs and a direct interaction of the receptors with SMAD3 and SMAD4 that is independent of T3-mediated transcriptional activity but requires residues in the receptor DNA binding domain. T3 reduces occupancy of SMAD-binding elements in response to TGF-ß, reducing histone acetylation and inhibiting transcription. In agreement with this transcriptional cross-talk, T3 is able to antagonize fibrotic processes in vivo. Liver fibrosis induced by carbon tetrachloride is attenuated by thyroid hormone administration to mice, whereas aged TR knockout mice spontaneously accumulate collagen. Furthermore, skin fibrosis induced by bleomycin administration is also reduced by the thyroid hormones. These findings define an important function of the thyroid hormone receptors and suggest TR ligands could have beneficial effects to block the progression of fibrotic diseases.
Asunto(s)
Cirrosis Hepática/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Triyodotironina/metabolismo , Animales , Bleomicina/efectos adversos , Bleomicina/farmacología , Intoxicación por Tetracloruro de Carbono/genética , Intoxicación por Tetracloruro de Carbono/metabolismo , Intoxicación por Tetracloruro de Carbono/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/genética , Cirrosis Hepática/patología , Ratones , Ratones Noqueados , Proteína smad3/genética , Proteína smad3/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Factor de Crecimiento Transformador beta/genética , Triyodotironina/genéticaRESUMEN
Nuclear corepressor 1 (NCoR) associates with nuclear receptors and other transcription factors leading to transcriptional repression. We show here that NCoR depletion enhances cancer cell invasion and increases tumor growth and metastatic potential in nude mice. These changes are related to repressed transcription of genes associated with increased metastasis and poor prognosis in patients. Strikingly, transient NCoR silencing leads to heterochromatinization and stable silencing of the NCoR gene, suggesting that NCoR loss can be propagated, contributing to tumor progression even in the absence of NCoR gene mutations. Down-regulation of the thyroid hormone receptor ß1 (TRß) appears to be associated with cancer onset and progression. We found that expression of TRß increases NCoR levels and that this induction is essential in mediating inhibition of tumor growth and metastasis by this receptor. Moreover, NCoR is down-regulated in human hepatocarcinomas and in the more aggressive breast cancer tumors, and its expression correlates positively with that of TRß. These data provide a molecular basis for the anticancer actions of this corepressor and identify NCoR as a potential molecular target for development of novel cancer therapies.
Asunto(s)
Homeostasis , Co-Represor 1 de Receptor Nuclear/genética , Anciano , Animales , Neoplasias de la Mama/genética , Línea Celular Tumoral , Proliferación Celular , Metilación de ADN/genética , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Heterocromatina/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Metástasis de la Neoplasia , Co-Represor 1 de Receptor Nuclear/metabolismo , Co-Represor 2 de Receptor Nuclear/metabolismo , Regiones Promotoras Genéticas/genética , ARN Interferente Pequeño/metabolismo , Receptores beta de Hormona Tiroidea , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
An increased neuroendocrine (NE) cell population in prostate cancer is associated with more aggressive disease and recurrence after androgen-deprivation therapy, although the mechanism responsible is unknown. In this study, we report that the treatment of LNCaP cells with epidermal growth factor (EGF) in the presence of LY294002, an inhibitor of the phosphoinositol 3'-kinase (PI3K)-AKT pathway, induced an increase of levels and activity of ErbB2. Under these conditions, we also observed cell survival and NE differentiation. When we treated with wortmannin, another PI3K inhibitor, or we knocked down PI3K or AKT isoforms in the presence of EGF, ErbB2 up-regulation was not observed, suggesting that the increase of ErbB2 induced by EGF plus LY294002 is not mediated by the PI3K-Akt pathway. Other targets of LY294002 were also discounted. We also show that ErbB2 up-regulation is directly involved in neuroendocine differentiation but not in cell survival as ErbB2 levels increased in parallel with NE differentiation marker levels, whereas ErbB2 knockdown reduced them; other NE differentiation inducers also increased the ErbB2 levels and the immunohistochemical analysis of prostate cancer samples showed colocalization of ErbB2 and chromogranin A. We found that, in LNCaP cells, EGF in combination with LY294002 increased ErbB2 levels by a PI3K/AKT-independent mechanism and that this increase was associated with the acquisition of a NE phenotype. These results suggest that is worth reconsidering ErbB2 as a drug target in prostate cancer and this should be kept in mind when designing new clinical schedules for the treatment of this disease.
Asunto(s)
Cromonas/farmacología , Factor de Crecimiento Epidérmico/farmacología , Morfolinas/farmacología , Células Neuroendocrinas/citología , Neoplasias de la Próstata/metabolismo , Receptor ErbB-2/biosíntesis , Andrógenos/deficiencia , Androstadienos/farmacología , Diferenciación Celular , Línea Celular Tumoral , Supervivencia Celular , Cromogranina A/metabolismo , Factor de Crecimiento Epidérmico/metabolismo , Humanos , Masculino , Células Neuroendocrinas/patología , Fosfatidilinositol 3-Quinasa/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , ARN Interferente Pequeño , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transducción de Señal/efectos de los fármacos , WortmaninaRESUMEN
The existence of molecular links that facilitate colorectal cancer (CRC) development in the population with type 2 diabetes (T2D) is supported by substantial epidemiological evidence. This review summarizes how the systemic, metabolic and hormonal imbalances from T2D alter CRC cell metabolism, signalling and gene expression as well as their reciprocal meshing, with an overview of CRC molecular subtypes and animal models to study the diabetes-CRC cancer links. Metabolic and growth factor checkpoints ensure a physiological cell proliferation rate compatible with limited nutrient supply. Hyperinsulinaemia and hyperleptinaemia in prediabetes and excess circulating glucose and lipids in T2D overcome formidable barriers for tumour development. Increased nutrient availability favours metabolic reprogramming, alters signalling and generates mutations and epigenetic modifications through increased reactive oxygen species and oncometabolites. The reciprocal control between metabolism and hormone signalling is lost in diabetes. Excess adipose tissue at the origin of T2D unbalances adipokine (leptin/adiponectin) secretion ratios and function and disrupts the insulin/IGF axes. Leptin/adiponectin imbalances in T2D are believed to promote proliferation and invasion of CRC cancer cells and contribute to inflammation, an important component of CRC tumourigenesis. Disruption of the insulin/IGF axes in T2D targets systemic and CRC cell metabolic reprogramming, survival and proliferation. Future research to clarify the molecular diabetes-CRC links will help to prevent CRC and reduce its incidence in the diabetic population and must guide therapeutic decisions.
Asunto(s)
Neoplasias Colorrectales , Diabetes Mellitus Tipo 2 , Adiponectina , Animales , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Diabetes Mellitus Tipo 2/patología , Humanos , Insulina , LeptinaRESUMEN
Obesity is the strongest known risk factor to develop type 2 diabetes (T2D) and both share a state of chronic, diffuse and low-grade inflammation, impaired immune responses and alterations in the composition and function of the microbiome. Notably, these hallmarks are shared with colorectal cancer (CRC), which is epidemiologically associated to obesity and T2D. Gut barrier damages in T2D destabilize the microbiome that metabolizes the diet and modulates the host immune response triggering inflammatory and proliferative pathways. In this review, we discuss the pathways altered by defects in the immune response and microbiota that may link T2D to CRC development. Stressed adipocytes, metabolic incongruity in blood and gut barrier failure with dysbiosis cooperate to establish imbalances between immune innate and adaptive cells and cytokines such as interleukin 6 (IL6) or TNFA that define low-grade diffuse inflammation in T2D. Inflammation drives tissue repair through proliferation and migration (critical mechanisms for tumourigenesis) and under physiological conditions feeds anti-inflammatory cytokine production to resolve the process. The disproportion in pro- vs anti-inflammatory cells and cytokines imposed by T2D will impact the tumour micro- and macro-environment, favouring tumour proliferation, angiogenesis and decreased immune responses. Complex bidirectional relationships between the metabolic environment of T2D, gut microbiota, and immune dysfunctions may favour tumour cell demands and will define the outcome. Animal models developed to study the relationships between T2D and CRC in the context of microbiota and immune system are discussed.
Asunto(s)
Neoplasias Colorrectales , Diabetes Mellitus Tipo 2 , Microbiota , Animales , Citocinas , Humanos , Inflamación , ObesidadRESUMEN
The present study was intended to gain additional information on the growth regulation of prostate by somatostatin (SRIF) and the intracellular events involved. The human prostate adenocarcinoma cell lines PC-3 and LNCaP produce SRIF and express subtypes 2 and 5 of SRIF receptors. The secretion of SRIF is related to the proliferative status of these cells; an inverse relationship exists between cell proliferation and the amount of secreted SRIF. Moreover, the growth of PC-3 cells is inhibited by SRIF overexpression and increased by blockage of endogenous SRIF. Coincident with the increase in SRIF secretion, the activity and levels of the SH2 domain containing protein tyrosine phosphatase (SHP)-1, present in PC-3 cells are augmented, but the effect can be partially prevented by neutralization of secreted endogenously SRIF. The activity of SHP-1 is also stimulated by the SRIF analog RC160. Overexpression of SHP-1 induces inhibition of PC-3 cell growth. SHP-1 is also present in normal prostate, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, and well differentiated adenocarcinoma. In contrast, no signal is detected in poorly differentiated prostate cancer. These findings demonstrate that SRIF inhibits PC-3 and LNCaP cell proliferation through an autocrine/paracrine SRIF loop. This effect could be mediated by activation of the tyrosine phosphatase SHP-1 detected in these cells as well as in human prostate and prostate cancer.
Asunto(s)
Comunicación Autocrina/fisiología , Carcinoma/patología , Neoplasias de la Próstata/patología , Proteínas Tirosina Fosfatasas/fisiología , Somatostatina/fisiología , Dominios Homologos src/fisiología , División Celular/fisiología , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Próstata/enzimología , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Proteína Tirosina Fosfatasa no Receptora Tipo 6 , Proteínas Tirosina Fosfatasas/química , Receptores de Somatostatina/metabolismo , Proteínas Tirosina Fosfatasas con Dominio SH2 , Somatostatina/metabolismo , Células Tumorales CultivadasRESUMEN
The primary focus of this investigation was to study the relationship between neuroendocrine (NE) differentiation and epidermal growth factor (EGF) because both have been implicated in the progression of prostate cancer. For this purpose, we used gefitinib and trastuzumab, which are inhibitors of EGF receptor (EGFR) and ErbB2, respectively. EGF prevents NE differentiation induced by androgen depletion. This effect is prevented by gefitinib, which blocks the activation of EGFR and ErbB2, stimulation of mitogen-activated protein kinase (MAPK), and cell proliferation induced by EGF. Conversely, trastuzumab does not inhibit the effect of EGF on EGFR phosphorylation, MAPK activity, cell proliferation, and NE differentiation, although it reduces ErbB2 levels specifically, suggesting that ErbB2 is not necessary to inhibit NE differentiation. Prevention of NE differentiation by EGF is mediated by a MAPK-dependent mechanism and requires constitutive Akt activation. The abrogation of the PI3K/Akt pathway changes the role of EGF from inhibitor to inductor of NE differentiation. We show that EGFR tyrosine kinase, MAPK, and PI3K inhibitors inhibit the cell proliferation stimulated by EGF but induce the acquisition of NE phenotype. Altogether, the present data should be borne in mind when designing new clinical schedules for the treatment of prostate cancer, including the use of ErbB receptors and associated signaling pathway inhibitors.