ABSTRACT
Components of the SWI/SNF chromatin remodeling complex, including BRG1 (also SMARCA4), are inactivated in cancer. Among other functions, SWI/SNF orchestrates the response to retinoid acid (RA) and glucocorticoids (GC) involving downregulation of MYC. The epigenetic drugs SAHA and azacytidine, as well as RA and GC, are currently being used to treat some malignancies but their therapeutic potential in lung cancer is not well established. Here we aimed to determine the possible therapeutic effects of azacytidine and SAHA (A/S) alone or in combination with GC plus RA (GC/RA) in lung cancers with either BRG1 inactivation or MYC amplification. In vitro, responses to GC/RA treatment were more effective in MYC-amplified cells. These effects were mediated by BRG1 and involved a reprogramming towards prodifferentiation gene expression signatures and downregulation of MYC. In MYC-amplified cells, administration of GC/RA enhanced the cell growth inhibitory effects of A/S which, in turn, accentuated the prodifferentiation features promoted by GC/RA. Finally, these treatments improved overall survival of mice orthotopically implanted with MYC-amplified, but not BRG1-mutant, cells and reduced tumor cell viability and proliferation. We propose that the combination of epigenetic treatments with retinoids and corticoids of MYC-driven lung tumors constitute a strategy for therapeutic intervention in this otherwise incurable disease.
Subject(s)
Azacitidine/pharmacology , Drug Resistance, Neoplasm/drug effects , Glucocorticoids/pharmacology , Hydroxamic Acids/pharmacology , Lung Neoplasms/drug therapy , Proto-Oncogene Proteins c-myc/metabolism , Tretinoin/pharmacology , Animals , Antimetabolites, Antineoplastic/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Proliferation/drug effects , DNA Helicases/genetics , DNA Methylation , Histone Deacetylase Inhibitors/pharmacology , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Mice , Mice, Nude , Mutation/genetics , Nuclear Proteins/genetics , Proto-Oncogene Proteins c-myc/genetics , Transcription Factors/genetics , Tumor Cells, Cultured , Vorinostat , Xenograft Model Antitumor AssaysABSTRACT
Neuroblastoma (NB) is a neoplasm of the sympathetic nervous system, and is the most common solid tumor of infancy. NBs are very heterogeneous, with a clinical course ranging from spontaneous regression to resistance to all current forms of treatment. High-risk patients need intense chemotherapy, and only 30-40% will be cured. Relapsed or metastatic tumors acquire multi-drug resistance, raising the need for alternative treatments. Owing to the diverse mechanisms that are responsible of NB chemoresistance, we aimed to target epigenetic factors that control multiple pathways to bypass therapy resistance. We found that the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4/BRG1) was consistently upregulated in advanced stages of NB, with high BRG1 levels being indicative of poor outcome. Loss-of-function experiments in vitro and in vivo showed that BRG1 is essential for the proliferation of NB cells. Furthermore, whole-genome transcriptome analysis revealed that BRG1 controls the expression of key elements of oncogenic pathways such as PI3K/AKT and BCL2, which offers a promising new combination therapy for high-risk NB.
Subject(s)
Cell Survival/genetics , DNA Helicases/genetics , Neuroblastoma/genetics , Nuclear Proteins/genetics , Transcription Factors/genetics , Transcriptome/genetics , Cell Death/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Neuroblastoma/pathology , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Signal Transduction/geneticsABSTRACT
Our rapidly growing knowledge about cancer genetics attests to the widespread occurrence of alterations at genes encoding different components of the SWI/SNF complex. This reveals an important new feature that sustains cancer development: the blockade of chromatin remodeling. Here, we provide an overview of our current knowledge on the gene alterations of chromatin-remodeling factors, and how they relate to cancer and human developmental diseases. We also consider the functional repercussions, particularly how the inactivation of the SWI/SNF complex impairs the appropriate cell response to nuclear receptor signaling, which, in turn, prevents cell differentiation and sustains cell growth independently of the environment.
Subject(s)
Cell Differentiation , Chromosomal Proteins, Non-Histone/genetics , Neoplasms/genetics , Transcription Factors/genetics , Animals , Child Development Disorders, Pervasive/genetics , Chromatin Assembly and Disassembly , Gene Expression Regulation, Neoplastic , Germ-Line Mutation , Humans , Receptors, Cytoplasmic and Nuclear/physiology , Signal TransductionSubject(s)
Diatrizoate , Fatty Acids , Pancreatitis/drug therapy , Propylene Glycols , Proteins/therapeutic use , Zein , Acute Disease , Adult , Animals , Dogs , Drug Combinations , Female , Humans , Male , Necrosis , Pancreatitis/pathology , Proteins/administration & dosageABSTRACT
Se presentan tres casos de pancreas aberrante, 2 situados en el estomago y 1 en la vesicula biliar, diagnosticados por estudio anatomopatologico. Se realiza una revision de los aspectos embriologicos fisio y anatomopatologicos, clinicos y terapeuticos de esta entidad
Subject(s)
Adult , Humans , Female , Congenital Abnormalities , PancreasABSTRACT
Se presentan tres casos de pancreas aberrante, 2 situados en el estomago y 1 en la vesicula biliar, diagnosticados por estudio anatomopatologico. Se realiza una revision de los aspectos embriologicos fisio y anatomopatologicos, clinicos y terapeuticos de esta entidad
