l-663536 and Neoplasms

Metastasis-associated protein 2 (MTA2) is a member of the metastasis-associated transcriptional regulator family and is a core component of the nucleosome remodeling and histone deacetylation complex. Despite growing evidence that MTA2 plays a crucial role in the tumorigenesis of certain cancers, no systematic pan-cancer analysis of MTA2 is available to date. Therefore, the aim of our study is to explore the prognostic value of MTA2 in 33 cancer types and to investigate its potential immune function.. by comprehensive use of databases from TCGA, GTEx, GEO, UCSC xena, cBioPortal, comPPI, GeneMANIA, TCIA, MSigDB, and PDB, we applied various bioinformatics approaches to investigate the potential role of MTA2, including analyzing the association of MTA2 with MSI, prognosis, gene mutation, and immune cell infiltration in different tumors. We constructed a nomogram in TCGA-LIHC, performed single-cell sequencing (scRNA-seq) analysis of MTA2 in hepatocellular carcinoma (HCC), and screened drugs for the treatment of HCC. Finally, immunohistochemical experiments were performed to verify the expression and prognostic value of MTA2 in HCC. In vitro experiments were employed to observe the growth inhibition effects of MK-886 on the HCC cell line HepG2.. The results suggested that MTA2 was highly expressed in most cancers, and MTA2 expression was associated with the prognosis of different cancers. In addition, MTA2 expression was associated with Tumor Mutation Burden (TMB) in 12 cancer types and MSI in 8 cancer types. Immunoassays indicated that MTA2 positively correlated with activated memory CD4 T cells and M0 macrophage infiltration levels in HCC. ScRNA-seq analysis based on the GEO dataset discovered that MTA2 was significantly expressed in T cells in HCC. Finally, the eXtreme Sum (Xsum) algorithm was used to screen the antitumor drug MK-886, and the molecular docking technique was utilized to reveal the binding capacity between MK-886 and the MTA2 protein. The results demonstrated excellent binding sites between them, which bind to each other through Π-alkyl and alkyl interaction forces. An immunohistochemistry experiment showed that MTA2 protein was highly expressed in HCC, and high MTA2 expression was associated with poor survival in HCC patients. MK-886 significantly inhibited the proliferation and induced cell death of HepG2 cells in a dose-dependent manner.. Our study demonstrated that MTA2 plays crucial roles in tumor progression and tumor immunity, and it could be used as a prognostic marker for various malignancies. MK-886 might be a powerful drug for HCC.

Topics: Carcinoma, Hepatocellular; Drug Evaluation, Preclinical; Early Detection of Cancer; Histone Deacetylases; Humans; Liver Neoplasms; Molecular Docking Simulation; Neoplasms; Prognosis; Repressor Proteins

Pretreatment with 5-LOX pathway inhibitor MK-886 potentiates cytotoxic effects of photodynamic therapy mediated by natural photosensitizer, hypericin. In this study, we focused on elucidating mechanisms beyond the increased efficacy of combined treatment.. Metabolic activity/viability, caspase-3 activation/mitochondrial membrane potential dissipation, intracellular hypericin level, glutathione level and redox status (NAD(P)H/oxidized flavins ratio) analyses, as well as drug efflux assays, were performed by flow cytometry. Changes in protein expression of ATP-binding cassette transporters, GDF-15 and other selected proteins were evaluated by Western blotting. Silencing of gdf-15 was carried out to verify its role in response to treatment.. MK-886 pretreatment led to a concentration-dependent increase in intracellular hypericin content, accompanied by changes in ATP-binding cassette transporters levels and efflux efficiency. Intracellular accumulation of cytokine GDF-15 correlated with increased cell death markers; however, the impact of gdf-15 silencing on the evaluated markers was negligible. A marked decrease in the glutathione level of a majority of cells was observed after more toxic combination treatment.. The significant increase in cell death markers after combination treatment confirms the potentiating effect of MK-886 on hypericin-mediated photodynamic therapy in HT-29 and MCF-7 cells. Although BCRP downregulation was not confirmed as leading mechanism responsible for elevated levels of hypericin content, changes in expression and efflux activity of ABC transporters caused by MK-886 suggest its potential in combination treatment with drugs that are substrates of these transporters, predominantly MRP1. However, complex cellular response to MK-886 pretreatment needs to be considered and further elucidated.

Topics: Anthracenes; ATP-Binding Cassette Transporters; Caspase 3; Cell Death; Cell Line, Tumor; Drug Synergism; Glutathione; Growth Differentiation Factor 15; Humans; Indoles; Membrane Potential, Mitochondrial; Neoplasms; Oxidation-Reduction; Perylene; Photochemotherapy; Photosensitizing Agents; RNA, Small Interfering

With a combination of inhibitors at less than their individual 'therapeutic' concentrations directed against dissimilar cellular hierarchical developmental controls and 'downstream' metabolic pathways, it may be possible to modulate the biologic behavior of malignantly transformed cells synergistically. Ideally the cumulative systemic toxicity of such a 'polytherapy' would be reduced.

Topics: Cell Division; Drug Therapy, Combination; Fluorouracil; Humans; Indoles; Lipoxygenase Inhibitors; Neoplasms; Tumor Cells, Cultured