Expression Array analysis of MTAP in HT080 cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE56112 | GEO | 2014/04/30
SECONDARY ACCESSION(S): PRJNA242440
REPOSITORIES: GEO
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Project description:Methylthioadenosine Phosphorylase (MTAP) is a tumor suppressor gene that encodes an enzyme responsible for the catabolism of the polyamine byproduct 5′deoxy-5′-methylthioadenosine (MTA). To elucidate the mechanism by which MTAP inhibits tumor formation, we have created isogenic MTAP+ and MTAP- HT1080 fibrosarcoma cells. In this experiment we have performed expression array analysis on MTAP-, MTAP+, and MTAP+ cells treated with the MTAP inhibitor MT-DADMe-ImmA. Three biological replicates of each sample were grown and analyzed. M- is MTAP-. M+ is MTAP+, and M+I is MTAP treated with inhibitor (48 hours).
2014-04-30 | E-GEOD-56112 | biostudies-arrayexpress
Project description:Type I Protein Arginine Methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginine (ADMA) residues on numerous protein substrates to modulate their activity. Type I PRMTs and many of their substrates have been implicated in human cancers, suggesting that inhibiting Type I PRMT activity offers a tractable approach for therapeutic intervention. The current report describes GSK3368715 (EPZ019997), a potent, reversible Type I PRMT inhibitor with anti-tumor activity against human cancer cells both in vitro and in vivo. GSK3368715 reduces ADMA on numerous substrates and concomitantly increases monomethyl (MMA) and symmetric dimethyl arginine (SDMA) levels. Inhibition of PRMT5, the major type II PRMT, attenuates this induction and produces synergistic antiproliferative effects in combination with GSK3368715 in cancer cells. PRMT5 activity is inhibited by 2-methylthioadenosine (MTA), a naturally occurring metabolite that accumulates in tumor cells deficient for the enzyme Methylthioadenosine Phosphorylase (MTAP). MTAP deletion in cancer cell lines correlates with sensitivity to GSK3368715, indicating a sufficient degree of PRMT5 inhibition from MTA accumulation to achieve a tumor cell-intrinsic combination. These data provide the rationale to explore MTAP status as a biomarker strategy for patient selection to maximize the anti-tumor activity of GSK3368715.
2019-08-15 | GSE126651 | GEO
Project description:Methylthioadenosine Phosphorylase (MTAP) loss is one of the most frequent genetic alterations in Glioblastoma and has been associated with poor clinical outcomes in several cancer types. Here we used patient derived glioblastoma cell lines and manipulated MTAP status to create isogenic pairs with which to study the effects of this alteration on epigenetics, gene expression, and cell identity
2019-11-01 | GSE130093 | GEO
Project description:The tumor microenvironment (TME) is a dynamic pseudoorgan that shapes the development and progression of cancers. It is a complex ecosystem shaped by interactions between tumor and stromal cells. Although the traditional focus has been on the paracrine communication mediated by protein messengers, recent attention has turned to the metabolic secretome in tumors. Metabolic enzymes, together with exchanged substrates and products, have emerged as potential biomarkers and therapeutic targets. However, traditional techniques for profiling secreted metabolites in complex cellular contexts are limited. Surface-enhanced Raman scattering (SERS) has emerged as a promising alternative due to its nontargeted nature and simplicity of operation. Although SERS has demonstrated its potential for detecting metabolites in biological settings, its application in deciphering metabolic interactions within multicellular systems like the TME remains underexplored. In this study, we introduce a SERS-based strategy to investigate the secreted purine metabolites of tumor cells lacking methylthioadenosine phosphorylase (MTAP), a common genetic event associated with poor prognosis in various cancers. Our SERS analysis reveals that MTAP-deficient cancer cells selectively produce methylthioadenosine (MTA), which is taken up and metabolized by fibroblasts. Fibroblasts exposed to MTA exhibit: i) molecular reprogramming compatible with cancer aggressiveness, ii) a significant production of purine derivatives that could be readily recycled by cancer cells, and iii) the capacity to secrete purine derivatives that induce macrophage polarization. Our study supports the potential of SERS for cancer metabolism research and reveals an unprecedented paracrine crosstalk that explains TME reprogramming in MTAP-deleted cancers.
2023-12-03 | GSE249082 | GEO
Project description:Abstract The aggressive nature and poor prognosis of lung cancer led us to explore the mechanisms driving disease progression. Utilizing our invasive cell-based model, we identified methylthioadenosine phosphorylase (MTAP) and confirmed its suppressive effects on tumorigenesis and metastasis, and patients with low MTAP expression displayed worse overall and progression-free survival. Mechanistically, accumulation of methylthioadenosine substrate in MTAP-deficient cells reduced the level of protein arginine methyltransferase 5 (PRMT5)-mediated symmetric dimethylarginine (sDMA) modification on proteins. Vimentin was revealed as a novel dimethyl-protein with less dimethylation level in response to MTAP loss. The sDMA modification on vimentin reduces its protein abundance and trivially affects its filamentous structure. In MTAP-loss cells, lower sDMA level prevents ubiquitination-mediated vimentin degradation, thereby stabilizing vimentin, contributing to cell invasion. This inverse association of the MTAP/PRMT5 axis with vimentin proteins was clinically corroborated. Taken together, we propose a novel mechanism of vimentin post-translational regulation and provide new insights in metastasis.
2022-05-31 | PXD031192 | Pride
Project description:Methylthioadenosine phosphorylase (MTAP), a key enzyme in the adenine and methionine salvage pathways, catalyzes the hydrolysis of methylthioadenosine (MTA), a compound suggested to affect pivotal cellular processes in part through the regulation of protein methylation. MTAP is expressed in a wide range of cell types and tissues and its deletion is common to cancer cells and in liver injury. The aim of this study was to investigate the proteome and methyl proteome alterations triggered by MTAP deficiency in liver cells to define novel regulatory mechanisms that may explain the pathogenic processes of liver diseases. iTRAQ analysis resulted in the identification of 216 differential proteins (p<0.05) that suggest deregulation of cellular pathways as those mediated by ERK or NFκB. R-methyl proteome analysis lead to the identification of 74 differentially methylated proteins between SK-Hep1 and SK-Hep1+ cells, including 116 new methylation sites. Restoring normal MTA levels in SK-Hep1+ cells parallels the specific methylation of 56 proteins, including KRT8, TGF and CTF8A, which provides a novel regulatory mechanism of their activity with potential implications in carcinogenesis. Inhibition of RNA binding proteins methylation is especially relevant upon accumulation of MTA. As an example, methylation of quaking protein in R242 and R256 in SK-Hep1+ cells may play a pivotal role in the regulation of its activity as indicated by the up-regulation of its target protein p27 kip1. The phenotype associated with a MTAP deficiency was further verified in the liver of MTAP+/- mice. Our data support that MTAP deficiency leads to MTA accumulation and deregulation of central cellular pathways, increasing proliferation and decreasing the susceptibility to chemotherapeutic drugs, which involves differential protein methylation.
2016-02-01 | PXD002957 | Pride
Project description:Previous studies implicated PRMT5 as a synthetic lethal target for MTAP deleted (MTAP del) cancers, however, the pharmacological characterization of small molecule inhibitors that recapitulate the synthetic lethal phenotype have not been described. MRTX1719 selectively inhibited PRMT5 in the presence of MTA, which is elevated in MTAP del cancers, and inhibited PRMT5-dependent activity and cell viability with >70-fold selectivity in HCT116 MTAP del compared to HCT116 MTAP WT cells. MRTX1719 demonstrated dose-dependent anti-tumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts, mouse or human hematopoietic cells. MRTX1719 demonstrated marked anti-tumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non-small cell lung cancer, and MPNST from the Phase 1/2 study. Significance: PRMT5 was identified as a synthetic lethal target for MTAP del cancers, however, previous PRMT5 inhibitors do not selectively target this genotype. The differentiated binding mode of MRTX1719 leverages the elevated MTA in MTAP del cancers and represents a promising therapy for the ~10% of cancer patients with this biomarker.
2023-08-09 | GSE240145 | GEO
Project description:Study hypothesized that oral supplementation of methylthioadenosine (MTA) would reduce the inflammatory response in mice exposed to an agent that induces colitis (DSS) and that this reduction in inflammatory response would lead to reduced clinical disease burden. Total RNA was collected from isolated colons of mice in the following treatment groups: untreated controls, DSS only, DSS+MTA
2011-12-20 | E-GEOD-34553 | biostudies-arrayexpress
Project description:MTAP is an enzyme and found deleted in various cancers, but its role in lung adenoacrcinoma is still unclear. This study sought to investigate the effects of MTAP on the biological behavior and global gene expression profiles in lung adenocacinoma cells. We used expression microarrays to identify the global gene alterations in lung adenocacinoma cell line, CL1-5 cells after ectopically expressing V5-tagged MTAP gene.
2022-05-12 | GSE160522 | GEO
Project description:Study hypothesized that oral supplementation of methylthioadenosine (MTA) would reduce the inflammatory response in mice exposed to an agent that induces colitis (DSS) and that this reduction in inflammatory response would lead to reduced clinical disease burden.
2011-12-20 | GSE34553 | GEO