Deregulation of protein methylation in melanoma

Limm, Katharina; Ott, Corinna; Wallner, Susanne; Mueller, Daniel; Oefner, Peter J.; Hellerbrand, Claus; Bosserhoff, Anja‐Katrin

doi:10.1016/j.ejca.2012.11.026

Cited by 50 publications

(58 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…62,63 In recent years, expression of MTAP in cancers has gained increasing interest. 13,64 Because of the accumulation of MTA in the tumor microenvironment of MTAP-negative malignancies, [25][26][27] we addressed the question whether MTA exerts inhibitory effects on T lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Stevens et al 26 reported secreted levels of 140 nM for melanoma specimens, while Limm et al 27 referred to intracellular concentrations of up to 100 mM. In vitro exposure of human T cells with MTA revealed a dual effect of MTA: To strongly inhibit polyclonally stimulated T cells or to suppress CTL effector functions in short-term assays (4-5 h), high MTA concentrations (100-500 mM) were needed.…”

Section: Discussionmentioning

confidence: 99%

“…23,24 A decreased expression of MTAP leads to MTA accumulation within tumor cells and their microenvironment. [25][26][27] The effect of MTA on tumor cells remains controversial: while intracellular concentrations of 0.5-5 mM MTA seem to promote tumor progression, [26][27][28] higher concentrations of MTA interfere with cell proliferation, tumor development, invasiveness and regulation of apoptosis, 29,30 MTA has been shown to be toxic to hematopoietic progenitor cells in vitro with an IC 50 equal or less than 1 mM. 31 In contrast, MTA has been tested in mice and rats and found to be non-toxic at high doses even when given over extended periods.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

et al. 2016

Self Cite

View full text Add to dashboard Cite

The immunosuppressive tumor microenvironment represents one of the main obstacles for immunotherapy of cancer. The tumor milieu is among others shaped by tumor metabolites such as 5 0 -deoxy-5 0 -methylthioadenosine (MTA). Increased intratumoral MTA levels result from a lack of the MTAcatabolizing enzyme methylthioadenosine phosphorylase (MTAP) in tumor cells and are found in various tumor entities. Here, we demonstrate that MTA suppresses proliferation, activation, differentiation, and effector function of antigen-specific T cells without eliciting cell death. Conversely, if MTA is added to highly activated T cells, MTA exerts cytotoxic effects on T cells. We identified the Akt pathway, a critical signal pathway for T cell activation, as a target of MTA, while, for example, p38 remained unaffected. Next, we provide evidence that MTA exerts its immunosuppressive effects by interfering with protein methylation in T cells. To confirm the relevance of the suppressive effects of exogenously added MTA on human T cells, we used an MTAP-deficient tumor cell-line that was stably transfected with the MTAPcoding sequence. We observed that T cells stimulated with MTAP-transfected tumor cells revealed a higher proliferative capacity compared to T cells stimulated with Mock-transfected cells. In conclusion, our findings reveal a novel immune evasion strategy of human tumor cells that could be of interest for therapeutic targeting.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Increased MTA Inhibits Protein Methylation in SK-Hep1 Cells, Remarkably RNA-Binding Proteins-MTA arises as a potential regulator of protein methylation, as has been demonstrated for rapidly accelerated fibrosarcoma in melanoma cells (48). Therefore, we wondered if the phenotypic differences between SK-Hep1 and SK-Hep1ϩ cells may involve changes in the overall protein methylation pattern in addition to the modifications in protein abundance already described.…”

Section: Mta Increases the Proliferation Rate Of Sk-hep1mentioning

confidence: 93%

“…The RAF protein has a PRMT5-specific GlyArgGly motif where R563 is dimethylated symmetrically, favoring its degradation (64). Accumulation of intracellular MTA inhibits RAF Arg 563 methylation increasing its stability, which might lead to ERK overactivation (48,63).…”

Section: Partial Deletion Of Mtap Increases the Sensitivity To Liver mentioning

confidence: 99%

Methylthioadenosine (MTA) Regulates Liver Cells Proteome and Methylproteome: Implications in Liver Biology and Disease

Bigaud

Corrales

2016

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

TMEFF2 and SARDH cooperate to modulate one‐carbon metabolism and invasion of prostate cancer cells

et al. 2013

View full text Add to dashboard Cite

BACKGROUND The transmembrane protein with epidermal growth factor and two follistatin motifs, TMEFF2, has been implicated in prostate cancer but its role in this disease is unclear. We recently demonstrated that the tumor suppressor role of TMEFF2 correlates, in part, with its ability to interact with sarcosine dehydrogenase (SARDH) and modulate sarcosine level. TMEFF2 overexpression inhibits sarcosine-induced invasion. Here, we further characterize the functional interaction between TMEFF2 and SARDH and their link with one-carbon (1-C) metabolism and invasion. METHODS RNA interference was used to study the effect of SARDH and/or TMEFF2 knockdown (KD) in invasion, evaluated using Boyden chambers. The dependence of invasion on 1-C metabolism was determined by examining sensitivity to methotrexate. Real-time PCR and western blot of subcellular fractions were used to study the effect of SARDH KD or TMEFF2 KD on expression of enzymes involved in one carbon (1-C) metabolism and on TMEFF2 expression and localization. Protein interactions were analyzed by mass-spectrometry. Cell viability and proliferation were measured by cell counting and MTT analysis. RESULTS While knocking down SARDH affects TMEFF2 subcellular localization, this effect is not responsible for the increased invasion observed in SARDH KD cells. Importantly, SARDH and/or TMEFF2 KD promote increased cellular invasion, sensitize the cell to methotrexate, render the cell resistant to invasion induced by sarcosine, a metabolite from the folate-mediated 1-C metabolism pathway, and affect the expression level of enzymes involved in that pathway. CONCLUSIONS Our findings define a role for TMEFF2 and the folate-mediated 1-C metabolism pathway in modulating cellular invasion.

show abstract

Deregulation of protein methylation in melanoma

Cited by 50 publications

References 34 publications

Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

Methylthioadenosine (MTA) Regulates Liver Cells Proteome and Methylproteome: Implications in Liver Biology and Disease

TMEFF2 and SARDH cooperate to modulate one‐carbon metabolism and invasion of prostate cancer cells

Contact Info

Product

Resources

About