The metabolite 5′-methylthioadenosine signals through the adenosine receptor A2B in melanoma

Limm, Katharina; Wallner, Susanne; Milenkovic, Vladimir M.; Wetzel, Christian H.; Bosserhoff, Anja‐Katrin

doi:10.1016/j.ejca.2014.07.005

Cited by 19 publications

(16 citation statements)

References 39 publications

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“…For comparison, the anionic metabolite, 2-hydroxyglutarate, has a distinctly intracellular presence, owing to its highly polar nature and absence of any substrate-specific transporters to facilitate its exit out of the cell. Both our data and structure-based-logic are supported by similar observations in other cancer models (Kamatani and Carson, 1980;Kirovski et al, 2011;Limm et al, 2014;Stevens et al, 2010). In fact, direct measurement of MTA secretion into culture medium out of MTAPdeleted cells was found to occur at a rate of 0.58 to 0.70 nmol/hr/mg of protein in a leukemia cell culture model (Kamatani and Carson, 1980) compared to < 0.1 for MTAP WT leukemia.…”

Section: In Vitro Mta Accumulation In Mtap-deleted Cells Is Primarilysupporting

confidence: 91%

“…Primary tumor environments are also characterized by high stromal content comprised of MTAP-WT cells (Figure 4). As MTA is a neutral nucleotide, both passive diffusion and movement via adenine transporters (Limm et al, 2014;Munshi et al, 1988) into MTAP-WT cells are possible, though the latter is much more likely (Iizasa et al, 1984;Munshi et al, 1988;Plagemann and Wohlhueter, 1980). Under this explanation, the net movement and metabolism of MTA by stromal cells makes the absence of any detectable increase in MTA in primary GBMs and CSF of MTAP-deleted tumors self-evident.…”

Section: Discussionmentioning

confidence: 99%

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Methylthioadenosine is Not Dramatically Elevated inMTAP-Homozygous Deleted Primary Glioblastomas

Barekatain

Yan

Ackroyd

et al. 2019

Preprint

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Highlights• Methylthioadenosine (MTA) is elevated in MTAP-deleted cancer cells in vitro, which provides a selective vulnerability to PRMT5 and MAT2A inhibitors • Accumulation of MTA in MTAP-deleted cancer cells is predominately extracellular, suggesting active secretion of MTA.• MTAP-deleted primary human glioblastoma tumors show minimal intratumoral elevations of MTA, which is likely explained by secretion and metabolism by MTAP-competent stromal cells. SUMMARYHomozygous deletion of the CDK2NA locus frequently results in co-deletion of methylthioadenosine phosphorylase (MTAP) in many fatal cancers such as glioblastoma multiforme (GBM), resulting in elevations of the substrate metabolite, methylthioadenosine (MTA). To capitalize on such accumulations, therapeutic targeting of protein arginine methyltransferase 5 (PRMT5) and methionine adenosyl transferase (MAT2A) are ongoing. While extensively corroborated in vitro, the clinical efficacy of these strategies ultimately relies on equally significant accumulations of MTA in human tumors.Here, we show that in vitro accumulation of MTA is a predominately extracellular phenomenon, indicating secretion of MTA from MTAP-deleted cells. In primary human GBMs, we find that MTA levels are not significantly higher in MTAP-deleted compared to MTAP-intact tumors or normal brain tissue. Together, these findings highlight the metabolic discrepancies between in vitro models and primary human tumors and should thus be carefully considered in the development of the precision therapies targeting MTAP-homozygous deleted GBM.

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Section: In Vitro Mta Accumulation In Mtap-deleted Cells Is Primarilysupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Methylthioadenosine is Not Dramatically Elevated inMTAP-Homozygous Deleted Primary Glioblastomas

Barekatain

Yan

Ackroyd

et al. 2019

Preprint

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“…Hypermethylation was associated with the deregulation of fibrillin‐1 (FBN1) that is a major component of microfibrils, and it can mediate cell adhesion in melanoma cells . ADORA2B has been identified as specific receptor for 5’‐methylthioadenosine (MTA) that can affect cell invasiveness in melanoma cells . Neural cell adhesion molecule L1 (CHL1) is frequently down‐regulated in different types of tumors, and it is verified to inhibit invasive growth and able to suppress further metastatic spread .…”

Section: Discussionmentioning

confidence: 98%

DNA hypermethylation is associated with invasive phenotype of malignant melanoma

Koroknai

Szász

Hernández-Vargas

et al. 2019

Experimental Dermatology

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Tumor cell invasion is one of the key processes during cancer progression, leading to life-threatening metastatic lesions in melanoma. As methylation of cancer-related genes plays a fundamental role during tumorigenesis and may lead to cellular plasticity which promotes invasion, our aim was to identify novel epigenetic markers on selected invasive melanoma cells. Using Illumina BeadChip assays and Affymetrix Human Gene 1.0 microarrays, we explored the DNA methylation landscape of selected invasive melanoma cells and examined the impact of DNA methylation on gene expression patterns. Our data revealed predominantly hypermethylated genes in the invasive cells affecting the neural crest differentiation pathway and regulation of the actin cytoskeleton. Integrative analysis of the methylation and gene expression profiles resulted in a cohort of hypermethylated genes (IL12RB2, LYPD6B, CHL1, SLC9A3, BAALC, FAM213A, SORCS1, GPR158, FBN1 and ADORA2B) with decreased expression. On the other hand, hypermethylation in the gene body of the EGFR and RBP4 genes was positively correlated with overexpression of the genes. We identified several methylation changes that can have role during melanoma progression, including hypermethylation of the promoter regions of the ARHGAP22 and NAV2 genes that are commonly altered in locally invasive primary melanomas as well as during metastasis. Interestingly, the down-regulation of the methylcytosine dioxygenase TET2 gene, which regulates DNA methylation, was associated with hypermethylated promoter region of the gene. This can probably lead to the observed global hypermethylation pattern of invasive cells and might be one of the key changes during the development of malignant melanoma cells. K E Y W O R D S cell invasion, DNA methylation, gene body, malignant melanoma, TET2

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“…TRPV1 receptors act as Ca 2+ ion channels in sensory nerves, contributing to chemotaxis, bronchoconstriction, mucous secretion, airway irritation and the urge to cough [36, 37]. Recently, methylthioadenosine (also contributing uniquely to CV1) was found to signal through the GPCR adenosine receptor A2B (A2BAR), activating the protein kinase C cascade [38] and, therefore, potentially TRPV1 [39]. A2BAR is present on sensory nerves [40] and is implicated in bronchoconstriction and cytokine release [41].…”

Section: Discussionmentioning

confidence: 99%

Metabolomics analysis identifies different metabotypes of asthma severity

et al. 2017

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In this study, we sought to determine whether asthma has a metabolic profile and whether this profile is related to disease severity.We characterised the serum from 22 healthy individuals and 54 asthmatics (12 mild, 20 moderate, 22 severe) using liquid chromatography–high-resolution mass spectrometry-based metabolomics. Selected metabolites were confirmed by targeted mass spectrometry assays of eicosanoids, sphingolipids and free fatty acids.We conclusively identified 66 metabolites; 15 were significantly altered with asthma (p≤0.05). Levels of dehydroepiandrosterone sulfate, cortisone, cortisol, prolylhydroxyproline, pipecolate and N-palmitoyltaurine correlated significantly (p<0.05) with inhaled corticosteroid dose, and were further shifted in individuals treated with oral corticosteroids. Oleoylethanolamide increased with asthma severity independently of steroid treatment (p<0.001). Multivariate analysis revealed two patterns: 1) a mean difference between controls and patients with mild asthma (p=0.025), and 2) a mean difference between patients with severe asthma and all other groups (p=1.7×10−4). Metabolic shifts in mild asthma, relative to controls, were associated with exogenous metabolites (e.g. dietary lipids), while those in moderate and severe asthma (e.g. oleoylethanolamide, sphingosine-1-phosphate, N-palmitoyltaurine) were postulated to be involved in activating the transient receptor potential vanilloid type 1 (TRPV1) receptor, driving TRPV1-dependent pathogenesis in asthma.Our findings suggest that asthma is characterised by a modest systemic metabolic shift in a disease severity-dependent manner, and that steroid treatment significantly affects metabolism.

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The metabolite 5′-methylthioadenosine signals through the adenosine receptor A2B in melanoma

Cited by 19 publications

References 39 publications

Methylthioadenosine is Not Dramatically Elevated inMTAP-Homozygous Deleted Primary Glioblastomas

Methylthioadenosine is Not Dramatically Elevated inMTAP-Homozygous Deleted Primary Glioblastomas

DNA hypermethylation is associated with invasive phenotype of malignant melanoma

Metabolomics analysis identifies different metabotypes of asthma severity

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