Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 35
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
Gastroenterology ; 160(6): 1947-1960, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33617889

RESUMEN

The cancer stem cell (CSC) concept emerged from the recognition of inherent tumor heterogeneity and suggests that within a given tumor, in analogy to normal tissues, there exists a cellular hierarchy composed of a minority of more primitive cells with enhanced longevity (ie, CSCs) that give rise to shorter-lived, more differentiated cells (ie, cancer bulk populations), which on their own are not capable of tumor perpetuation. CSCs can be responsible for cancer therapeutic resistance to conventional, targeted, and immunotherapeutic treatment modalities, and for cancer progression through CSC-intrinsic molecular mechanisms. The existence of CSCs in colorectal cancer (CRC) was first established through demonstration of enhanced clonogenicity and tumor-forming capacity of this cell subset in human-to-mouse tumor xenotransplantation experiments and subsequently confirmed through lineage-tracing studies in mice. Surface markers for CRC CSC identification and their prospective isolation are now established. Therefore, the application of single-cell omics technologies to CSC characterization, including whole-genome sequencing, RNA sequencing, and epigenetic analyses, opens unprecedented opportunities to discover novel targetable molecular pathways and hence to develop novel strategies for CRC eradication. We review recent advances in this field and discuss the potential implications of next-generation CSC analyses for currently approved and experimental targeted CRC therapies.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Biología Computacional , Células Madre Neoplásicas , Animales , Antineoplásicos Inmunológicos/uso terapéutico , Carcinogénesis , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Biología Computacional/métodos , Resistencia a Antineoplásicos , Genómica , Humanos , Inmunoterapia , Terapia Molecular Dirigida , Análisis de la Célula Individual
2.
J Biol Chem ; 295(22): 7774-7788, 2020 05 29.
Artículo en Inglés | MEDLINE | ID: mdl-32317280

RESUMEN

Glioblastoma multiforme (GBM) is a malignant brain tumor with a poor prognosis resulting from tumor resistance to anticancer therapy and a high recurrence rate. Compelling evidence suggests that this is driven by subpopulations of cancer stem cells (CSCs) with tumor-initiating potential. ABC subfamily B member 5 (ABCB5) has been identified as a molecular marker for distinct subsets of chemoresistant tumor-initiating cell populations in diverse human malignancies. In the current study, we examined the potential role of ABCB5 in growth and chemoresistance of GBM. We found that ABCB5 is expressed in primary GBM tumors, in which its expression was significantly correlated with the CSC marker protein CD133 and with overall poor survival. Moreover, ABCB5 was also expressed by CD133-positive CSCs in the established human U-87 MG, LN-18, and LN-229 GBM cell lines. Antibody- or shRNA-mediated functional ABCB5 blockade inhibited proliferation and survival of GBM cells and sensitized them to temozolomide (TMZ)-induced apoptosis in vitro Likewise, in in vivo human GBM xenograft experiments with immunodeficient mice, mAb treatment inhibited growth of mutant TP53, WT PTEN LN-229 tumors, and sensitized LN-229 tumors to TMZ therapy. Mechanistically, we demonstrate that ABCB5 blockade inhibits TMZ-induced G2/M arrest and augments TMZ-mediated cell death. Our results identify ABCB5 as a GBM chemoresistance marker and point to the potential utility of targeting ABCB5 to improve current GBM therapies.


Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP , Anticuerpos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas , Resistencia a Antineoplásicos/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Glioblastoma , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Proteínas de Neoplasias , ARN Interferente Pequeño , Temozolomida/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Ratones , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Nature ; 511(7509): 353-7, 2014 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-25030174

RESUMEN

Corneal epithelial homeostasis and regeneration are sustained by limbal stem cells (LSCs), and LSC deficiency is a major cause of blindness worldwide. Transplantation is often the only therapeutic option available to patients with LSC deficiency. However, while transplant success depends foremost on LSC frequency within grafts, a gene allowing for prospective LSC enrichment has not been identified so far. Here we show that ATP-binding cassette, sub-family B, member 5 (ABCB5) marks LSCs and is required for LSC maintenance, corneal development and repair. Furthermore, we demonstrate that prospectively isolated human or murine ABCB5-positive LSCs possess the exclusive capacity to fully restore the cornea upon grafting to LSC-deficient mice in xenogeneic or syngeneic transplantation models. ABCB5 is preferentially expressed on label-retaining LSCs in mice and p63α-positive LSCs in humans. Consistent with these findings, ABCB5-positive LSC frequency is reduced in LSC-deficient patients. Abcb5 loss of function in Abcb5 knockout mice causes depletion of quiescent LSCs due to enhanced proliferation and apoptosis, and results in defective corneal differentiation and wound healing. Our results from gene knockout studies, LSC tracing and transplantation models, as well as phenotypic and functional analyses of human biopsy specimens, provide converging lines of evidence that ABCB5 identifies mammalian LSCs. Identification and prospective isolation of molecularly defined LSCs with essential functions in corneal development and repair has important implications for the treatment of corneal disease, particularly corneal blindness due to LSC deficiency.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismo , Limbo de la Córnea/citología , Limbo de la Córnea/fisiología , Regeneración , Células Madre/metabolismo , Cicatrización de Heridas , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/deficiencia , Transportadoras de Casetes de Unión a ATP/deficiencia , Animales , Apoptosis , Biomarcadores/metabolismo , Diferenciación Celular , Proliferación Celular , Femenino , Humanos , Masculino , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Trasplante de Células Madre , Células Madre/citología , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo
4.
J Biol Chem ; 293(28): 11166-11178, 2018 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-29789423

RESUMEN

ABC member B5 (ABCB5) mediates multidrug resistance (MDR) in diverse malignancies and confers clinically relevant 5-fluorouracil resistance to CD133-expressing cancer stem cells in human colorectal cancer (CRC). Because of its recently identified roles in normal stem cell maintenance, we hypothesized that ABCB5 might also serve MDR-independent functions in CRC. Here, in a prospective clinical study of 142 CRC patients, we found that ABCB5 mRNA transcripts previously reported not to be significantly expressed in healthy peripheral blood mononuclear cells are significantly enriched in patient peripheral blood specimens compared with non-CRC controls and correlate with CRC disease progression. In human-to-mouse CRC tumor xenotransplantation models that exhibited circulating tumor mRNA, we observed that cancer-specific ABCB5 knockdown significantly reduced detection of these transcripts, suggesting that the knockdown inhibited tumor invasiveness. Mechanistically, this effect was associated with inhibition of expression and downstream signaling of AXL receptor tyrosine kinase (AXL), a proinvasive molecule herein shown to be produced by ABCB5-positive CRC cells. Importantly, rescue of AXL expression in ABCB5-knockdown CRC tumor cells restored tumor-specific transcript detection in the peripheral blood of xenograft recipients, indicating that ABCB5 regulates CRC invasiveness, at least in part, by enhancing AXL signaling. Our results implicate ABCB5 as a critical determinant of CRC invasiveness and suggest that ABCB5 blockade might represent a strategy in CRC therapy, even independently of ABCB5's function as an MDR mediator.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Movimiento Celular , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Animales , Apoptosis , Estudios de Casos y Controles , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Invasividad Neoplásica , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Genes Dev ; 24(6): 537-42, 2010 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-20194433

RESUMEN

Estrogen-related receptor alpha (ERRalpha) and proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) play central roles in the transcriptional control of energy homeostasis, but little is known about factors regulating their activity. Here we identified the homeobox protein prospero-related homeobox 1 (Prox1) as one such factor. Prox1 interacts with ERRalpha and PGC-1alpha, occupies promoters of metabolic genes on a genome-wide scale, and inhibits the activity of the ERRalpha/PGC-1alpha complex. DNA motif analysis suggests that Prox1 interacts with the genome through tethering to ERRalpha and other factors. Importantly, ablation of Prox1 and ERRalpha have opposite effects on the respiratory capacity of liver cells, revealing an unexpected role for Prox1 in the control of energy homeostasis.


Asunto(s)
Metabolismo Energético , Proteínas de Homeodominio/metabolismo , Receptores de Estrógenos/metabolismo , Transactivadores/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Células Hep G2 , Proteínas de Homeodominio/genética , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Receptores de Estrógenos/genética , Regulón/genética , Transactivadores/genética , Factores de Transcripción , Proteínas Supresoras de Tumor/genética , Receptor Relacionado con Estrógeno ERRalfa
6.
PLoS Genet ; 7(6): e1002143, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21731503

RESUMEN

Metabolic homeostasis and circadian rhythms are closely intertwined biological processes. Nuclear receptors, as sensors of hormonal and nutrient status, are actively implicated in maintaining this physiological relationship. Although the orphan nuclear receptor estrogen-related receptor α (ERRα, NR3B1) plays a central role in the control of energy metabolism and its expression is known to be cyclic in the liver, its role in temporal control of metabolic networks is unknown. Here we report that ERRα directly regulates all major components of the molecular clock. ERRα-null mice also display deregulated locomotor activity rhythms and circadian period lengths under free-running conditions, as well as altered circulating diurnal bile acid and lipid profiles. In addition, the ERRα-null mice exhibit time-dependent hypoglycemia and hypoinsulinemia, suggesting a role for ERRα in modulating insulin sensitivity and glucose handling during the 24-hour light/dark cycle. We also provide evidence that the newly identified ERRα corepressor PROX1 is implicated in rhythmic control of metabolic outputs. To help uncover the molecular basis of these phenotypes, we performed genome-wide location analyses of binding events by ERRα, PROX1, and BMAL1, an integral component of the molecular clock. These studies revealed the existence of transcriptional regulatory loops among ERRα, PROX1, and BMAL1, as well as extensive overlaps in their target genes, implicating these three factors in the control of clock and metabolic gene networks in the liver. Genomic convergence of ERRα, PROX1, and BMAL1 transcriptional activity thus identified a novel node in the molecular circuitry controlling the daily timing of metabolic processes.


Asunto(s)
Proteínas de Homeodominio/metabolismo , Hígado/metabolismo , Receptores de Estrógenos/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Animales , Ácidos y Sales Biliares/sangre , Glucemia/análisis , Western Blotting , Proteínas CLOCK/metabolismo , Células COS , Chlorocebus aethiops , Colesterol/sangre , Ritmo Circadiano , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Gluconeogénesis , Glucólisis , Células Hep G2 , Proteínas de Homeodominio/genética , Homeostasis , Humanos , Insulina/sangre , Hígado/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora , Fotoperiodo , Regiones Promotoras Genéticas , Unión Proteica , Interferencia de ARN , Receptores de Estrógenos/genética , Triglicéridos/sangre , Proteínas Supresoras de Tumor/genética , Receptor Relacionado con Estrógeno ERRalfa
7.
J Med Chem ; 67(6): 4707-4725, 2024 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-38498998

RESUMEN

Despite decades of research on new diffuse intrinsic pontine glioma (DIPG) treatments, little or no progress has been made on improving patient outcomes. In this work, we explored novel scaffold modifications of M4K2009, a 3,5-diphenylpyridine ALK2 inhibitor previously reported by our group. Here we disclose the design, synthesis, and evaluation of a first-in-class set of 5- to 7-membered ether-linked and 7-membered amine-linked constrained inhibitors of ALK2. This rigidification strategy led us to the discovery of the ether-linked inhibitors M4K2308 and M4K2281 and the amine-linked inhibitors M4K2304 and M4K2306, each with superior potency against ALK2. Notably, M4K2304 and M4K2306 exhibit exceptional selectivity for ALK2 over ALK5, surpassing the reference compound. Preliminary studies on their in vivo pharmacokinetics, including blood-brain barrier penetration, revealed that these constrained scaffolds have favorable exposure and do open a novel chemical space for further optimization and future evaluation in orthotopic models of DIPG.


Asunto(s)
Aminas , Éteres , Humanos
8.
Biochem Biophys Res Commun ; 436(3): 536-42, 2013 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-23770371

RESUMEN

ABCB5 is a multidrug resistance (MDR) member of the ATP-binding cassette (ABC) superfamily of active transporters and represents a marker for chemoresistant malignant melanoma-initiating cells. ABCB5 expression is closely linked to tumorigenicity and progression of diverse human malignancies, including melanoma, and is functionally required for tumor growth. Here, we genotyped 585 melanoma cases and 605 age-matched controls for 44 ABCB5 tagging single nucleotide polymorphisms (SNPs) to span a region covering 108.2kb of the gene on the 7p21.1 locus. We identified three SNPs that were associated with decreased melanoma risk in additive models: rs10231520 (OR: 0.83, 95% CI: 0.70-0.98), rs17817117 (OR: 0.82, 95% CI: 0.68-0.98), and rs2301641 (OR: 0.83, 95% CI: 0.69-0.98). Additionally, the rs2301641 SNP was associated with non-red compared to red hair color (OR: 0.38, 95% CI: 0.14-1.03) in controls. Twelve human melanoma cell lines were genotyped for the rs2301641 SNP, which encodes a non-synonymous ABCB5 amino acid change (K115E). Functional studies revealed that the E form associated with lower melanoma risk correlated significantly with decreased ABCB5 transport capacity (P<0.01) and increased melanin production (P<0.05). Our results identify novel associations of the ABCB5 K115E polymorphism with human pigmentation phenotype and melanoma risk and point to potential functional roles of ABCB5 in melanomagenesis. Moreover, they provide a first example that functional variation in a prospective cancer stem cell marker can be associated with disease risk for the corresponding malignancy.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Regulación Neoplásica de la Expresión Génica , Melaninas/metabolismo , Melanoma/patología , Pigmentación/genética , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Adulto , Anciano , Alelos , Estudios de Casos y Controles , Línea Celular Tumoral , Femenino , Estudios de Asociación Genética , Sitios Genéticos , Color del Cabello/genética , Humanos , Masculino , Melaninas/genética , Persona de Mediana Edad , Oportunidad Relativa , Fenotipo , Polimorfismo de Nucleótido Simple , Factores de Riesgo
9.
J Org Chem ; 78(11): 5705-10, 2013 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-23700973

RESUMEN

The reaction of 3-halo-4-aminopyridines with acyl chlorides and triethylamine is described. The pyridin-4-yl α-substituted acetamide products were obtained in moderate to high yields. The presented rearrangement reaction, in which the presumed N-acylated intermediate reacts intramolecularly via nucleophilic aromatic substitution, results in a formal two-carbon insertion.


Asunto(s)
Acetamidas/síntesis química , Hidrocarburos Clorados/química , Piridinas/química , Acetamidas/química , Cristalografía por Rayos X , Etilaminas/química , Modelos Moleculares , Estructura Molecular
10.
ACS Med Chem Lett ; 14(2): 199-210, 2023 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-36793435

RESUMEN

B cell lymphoma 6 (BCL6), a highly regulated transcriptional repressor, is deregulated in several forms of non-Hodgkin lymphoma (NHL), most notably in diffuse large B-cell lymphoma (DLBCL). The activities of BCL6 are dependent on protein-protein interactions with transcriptional co-repressors. To find new therapeutic interventions addressing the needs of patients with DLBCL, we initiated a program to identify BCL6 inhibitors that interfere with co-repressor binding. A virtual screen hit with binding activity in the high micromolar range was optimized by structure-guided methods, resulting in a novel and highly potent inhibitor series. Further optimization resulted in the lead candidate 58 (OICR12694/JNJ-65234637), a BCL6 inhibitor with low nanomolar DLBCL cell growth inhibition and an excellent oral pharmacokinetic profile. Based on its overall favorable preclinical profile, OICR12694 is a highly potent, orally bioavailable candidate for testing BCL6 inhibition in DLBCL and other neoplasms, particularly in combination with other therapies.

11.
Cell Metab ; 5(5): 345-56, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17488637

RESUMEN

Orphan nuclear receptor ERRalpha (NR3B1) is recognized as a key regulator of mitochondrial biogenesis, but it is not known whether ERRalpha and other ERR isoforms play a broader role in cardiac energetics and function. We used genome-wide location analysis and expression profiling to appraise the role of ERRalpha and gamma (NR3B3) in the adult heart. Our data indicate that the two receptors, acting as nonobligatory heterodimers, target a common set of promoters involved in the uptake of energy substrates, production and transport of ATP across the mitochondrial membranes, and intracellular fuel sensing, as well as Ca(2+) handling and contractile work. Motif-finding algorithms assisted by functional studies indicated that ERR target promoters are enriched for NRF-1, CREB, and STAT3 binding sites. Our study thus reveals that the ERRs orchestrate a comprehensive cardiac transcriptional program and further suggests that modulation of ERR activities could be used to manage cardiomyopathies.


Asunto(s)
Regulación de la Expresión Génica , Genoma/genética , Corazón/fisiología , Regiones Promotoras Genéticas/fisiología , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Estrógenos/metabolismo , Animales , Inmunoprecipitación de Cromatina , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Perfilación de la Expresión Génica , Masculino , Ratones , Ratones Noqueados , Factor 1 Relacionado con NF-E2/metabolismo , Regiones Promotoras Genéticas/genética , Factor de Transcripción STAT3/metabolismo , Receptor Relacionado con Estrógeno ERRalfa
12.
Cell Rep ; 40(6): 111166, 2022 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-35947947

RESUMEN

The corneal epithelium is renowned for high regenerative potential, which is dependent on the coordinated function of its diverse progenitor subpopulations. However, the molecular pathways governing corneal epithelial progenitor differentiation are incompletely understood. Here, we identify a highly proliferative limbal epithelial progenitor subpopulation characterized by expression of basal cell adhesion molecule (BCAM) that is capable of holocone formation and corneal epithelial sheet generation. BCAM-positive cells can be found among ABCB5-positive limbal stem cells (LSCs) as well as among ABCB5-negative limbal epithelial cell populations. Mechanistically, we show that BCAM is functionally required for cellular migration and differentiation and that its expression is regulated by the transcription factor p63. In aggregate, our study identifies limbal BCAM expression as a marker of highly proliferative corneal epithelial progenitor cells and defines the role of BCAM as a critical molecular mediator of corneal epithelial differentiation.


Asunto(s)
Epitelio Corneal , Limbo de la Córnea , Diferenciación Celular , Células Cultivadas , Córnea , Células Epiteliales/metabolismo , Limbo de la Córnea/metabolismo , Células Madre/metabolismo
14.
Biochem Biophys Res Commun ; 402(4): 711-7, 2010 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-20977885

RESUMEN

Circulating tumor cells (CTC) have been identified in several human malignancies, including malignant melanoma. However, whether melanoma CTC are tumorigenic and cause metastatic progression is currently unknown. Here, we isolate for the first time viable tumorigenic melanoma CTC and demonstrate that this cell population is capable of metastasis formation in human-to-mouse xenotransplantation experiments. The presence of CTC among peripheral blood mononuclear cells (PBMC) of murine recipients of subcutaneous (s.c.) human melanoma xenografts could be detected based on mRNA expression for human GAPDH and/or ATP-binding cassette subfamily B member 5 (ABCB5), a marker of malignant melanoma-initiating cells previously shown to be associated with metastatic disease progression in human patients. ABCB5 expression could also be detected in PBMC preparations from human stage IV melanoma patients but not healthy controls. The detection of melanoma CTC in human-to-mouse s.c. tumor xenotransplantation models correlated significantly with pulmonary metastasis formation. Moreover, prospectively isolated CTC from murine recipients of s.c. melanoma xenografts were capable of primary tumor initiation and caused metastasis formation upon xenotransplantation to secondary murine NOD-scid IL2Rγ(null) recipients. Our results provide initial evidence that melanoma CTC are tumorigenic and demonstrate that CTC are capable of causing metastatic tumor progression. These findings suggest a need for CTC eradication to inhibit metastatic progression and provide a rationale for assessment of therapeutic responses of this tumorigenic cell population to promising emerging melanoma treatment modalities.


Asunto(s)
Transformación Celular Neoplásica/patología , Melanoma/patología , Células Neoplásicas Circulantes/patología , Neoplasias Cutáneas/patología , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/análisis , Animales , Biomarcadores de Tumor/análisis , Separación Celular , Humanos , Ratones , Ratones Desnudos , Metástasis de la Neoplasia , Trasplante de Neoplasias
15.
Clin Cancer Res ; 15(9): 3058-67, 2009 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-19383820

RESUMEN

PURPOSE: Dysregulation of the insulin-like growth factor-I receptor (IGF-IR) signaling pathway has been implicated in the development of many types of tumors, including prostate, colon, breast, pancreatic, ovarian, and sarcomas. Agents that inhibit IGF-IR activity may be useful in treatment of patients with various cancers. EXPERIMENTAL DESIGN: Kinase assays were used to identify a selective small-molecule inhibitor of IGF-IR activity. The effects of this compound on IGF-IR signaling, cell proliferation, and the cell cycle were determined using a panel of cell lines. Antitumor activity was evaluated in human tumor xenografts growing in athymic mice. Inhibition of IGF-IR and the closely related insulin receptor (IR) was measured in vivo, and the effect on glucose metabolism was evaluated. RESULTS: GSK1904529A selectively inhibits IGF-IR and IR with IC(50)s of 27 and 25 nmol/L, respectively. GSK1904529A blocks receptor autophosphorylation and downstream signaling, leading to cell cycle arrest. It inhibits the proliferation of cell lines derived from solid and hematologic malignancies, with multiple myeloma and Ewing's sarcoma cell lines being most sensitive. Oral administration of GSK1904529A decreases the growth of human tumor xenografts in mice, consistent with a reduction of IGF-IR phosphorylation in tumors. Despite the potent inhibitory activity of GSK1904529A on IR in vitro and in vivo, minimal effects on blood glucose levels are observed in animals at doses that show significant antitumor activity. CONCLUSION: GSK1904529A is a promising candidate for therapeutic use in IGF-IR-dependent tumors.


Asunto(s)
Antineoplásicos/farmacología , Imidazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Ácido 3-Hidroxibutírico/metabolismo , Animales , Apoptosis/efectos de los fármacos , Glucemia/metabolismo , Western Blotting , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Imidazoles/metabolismo , Masculino , Ratones , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Fosforilación/efectos de los fármacos , Piridinas/metabolismo , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/antagonistas & inhibidores , Receptor de Insulina/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
16.
J Med Chem ; 63(17): 10061-10085, 2020 09 10.
Artículo en Inglés | MEDLINE | ID: mdl-32787083

RESUMEN

There are currently no effective chemotherapeutic drugs approved for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric cancer resident in the pons region of the brainstem. Radiation therapy is beneficial but not curative, with the condition being uniformly fatal. Analysis of the genomic landscape surrounding DIPG has revealed that activin receptor-like kinase-2 (ALK2) constitutes a potential target for therapeutic intervention given its dysregulation in the disease. We adopted an open science approach to develop a series of potent, selective, orally bioavailable, and brain-penetrant ALK2 inhibitors based on the lead compound LDN-214117. Modest structural changes to the C-3, C-4, and C-5 position substituents of the core pyridine ring afforded compounds M4K2009, M4K2117, and M4K2163, each with a superior potency, selectivity, and/or blood-brain barrier (BBB) penetration profile. Robust in vivo pharmacokinetic (PK) properties and tolerability mark these inhibitors as advanced preclinical compounds suitable for further development and evaluation in orthotopic models of DIPG.


Asunto(s)
Receptores de Activinas Tipo I/antagonistas & inhibidores , Antineoplásicos/farmacología , Glioma Pontino Intrínseco Difuso/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Descubrimiento de Drogas , Femenino , Células HEK293 , Humanos , Masculino , Ratones SCID , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-Actividad
18.
Mol Endocrinol ; 22(3): 570-84, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18063693

RESUMEN

Interplay between different posttranslational modifications of transcription factors is an important mechanism to achieve an integrated regulation of gene expression. For the estrogen-related receptors (ERRs) alpha and gamma, regulation by posttranslational modifications is still poorly documented. Here we show that transcriptional repression associated with the ERR amino-terminal domains is mediated through sumoylation at a conserved phospho-sumoyl switch, psiKxEPxSP, that exists within a larger synergy control motif. Arginine substitution of the sumoylatable lysine residue or alanine substitution of a nearby phosphorylatable serine residue (serine 19 in ERRalpha) increased the transcriptional activity of both ERRalpha and -gamma. In addition, phospho-mimetic substitution of the serine residue with aspartate restored the sumoylation and transcriptional repression activity. The increased transcriptional activity of the sumoylation-deficient mutants was more pronounced in the presence of multiple adjacent ERR response elements. We also identified protein inhibitor of activated signal transducer and activator of transcription y as an interacting partner and a small ubiquitin-related modifier E3 ligase for ERRalpha. Importantly, analysis with a phospho-specific antibody revealed that sumoylation of ERRalpha in mouse liver requires phosphorylation of serine 19. Taken together, these results show that the interplay of phosphorylation and sumoylation in the amino-terminal domain provides an additional mechanism to regulate the transcriptional activity of ERRalpha and -gamma.


Asunto(s)
Regulación de la Expresión Génica/fisiología , Receptores Citoplasmáticos y Nucleares/genética , Receptores de Estrógenos/genética , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/fisiología , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Sitios de Unión , Células COS , Chlorocebus aethiops , ADN/química , ADN/genética , Ensayo de Cambio de Movilidad Electroforética , Células HeLa , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Fosforilación , Proteínas de Unión a Poli-ADP-Ribosa , Proteínas Inhibidoras de STAT Activados/fisiología , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Estrógenos/metabolismo , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/genética , Transcripción Genética , Receptor Relacionado con Estrógeno ERRalfa
19.
Mol Cancer ; 7: 49, 2008 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-18533032

RESUMEN

BACKGROUND: The transcription factor GATA3 has recently been shown to be necessary for mammary gland morphogenesis and luminal cell differentiation. There is also an increasing body of data linking GATA3 to the estrogen receptor alpha (ERalpha) pathway. Among these it was shown that GATA3 associates with the promoter of the ERalpha gene and ERalpha can reciprocally associate with the GATA3 gene. GATA3 has also been directly implicated in a differentiated phenotype in mouse models of mammary tumourigenesis. The purpose of our study was to compare coexpressed genes, by meta-analysis, of GATA3 and relate these to a similar analysis for ERalpha to determine the depth of overlap. RESULTS: We have used a newly described method of meta-analysis of multiple cancer studies within the Oncomine database, focusing here predominantly upon breast cancer studies. We demonstrate that ERalpha and GATA3 reciprocally have the highest overlap with one another. Furthermore, we show that when both coexpression meta-analysis lists for ERalpha and GATA3 are compared there is a significant overlap between both and, like ERalpha, GATA3 coexpresses with ERalpha pathway partners such as pS2 (TFF1), TFF3, FOXA1, BCL2, ERBB4, XBP1, NRIP1, IL6ST, keratin 18(KRT18) and cyclin D1 (CCND1). Moreover, as these data are derived from human tumour samples this adds credence to previous cell-culture or murine based studies. CONCLUSION: GATA3 is hypothesized to be integral to the ERalpha pathway given the following: (1) The large overlap of coexpressed genes as seen by meta-analysis, between GATA3 and ERalpha, (2) The highest coexpressing gene for GATA3 was ERalpha and vice-versa, (3) GATA3, like ERalpha, coexpresses with many well-known ERalpha pathway partners such as pS2.


Asunto(s)
Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/genética , Factor de Transcripción GATA3/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Sitios de Unión , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Reporteros , Humanos , Regiones Promotoras Genéticas/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
20.
J Carcinog ; 7: 6, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-19008565

RESUMEN

The GATA3 transcription factor is expressed in many tissues such as the immune system, kidney, brain, endometrium, and mammary epithelial cells. As such it must co-ordinate a diverse transcriptional program to achieve specific outcomes in different tissues. One of the most interesting questions raised is whether GATA3 will be involved in the same pathways in every tissue or will be involved in distinct regulatory networks within different tissue types? While previous studies may imply the latter, with some known targets of GATA3 perhaps being specific to cell-type or tissue-type, the question has not been systematically addressed until now. With the advent of techniques such as co-expression meta-analysis a better understanding of the pathway partners of GATA3 can be obtained and specifically the partners within different tissue types can be found, yielding leads for future studies. Here, a recent technique of meta-analysis from the Oncomine database has been employed to probe this very question. Data obtained implies that GATA3 is involved in distinct pathways in different tissue types.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA