Direct and tumor microenvironment mediated influences of 5′‐deoxy‐5′‐(methylthio)adenosine on tumor progression of malignant melanoma

Stevens, Axel Peter; Spangler, Barbara; Wallner, Susanne; Kreutz, Marina; Dettmer, Katja; Oefner, Peter J.; Bosserhoff, Anja‐Katrin

doi:10.1002/jcb.21984

Cited by 52 publications

(67 citation statements)

References 32 publications

(38 reference statements)

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“…The value of MTAP as a therapeutic target has been questioned, and MTA in blood has been suggested as a biomarker for cancer (17). Here, we demonstrate a robust suppression of lung cancer growth and metastases in mouse xenografts by systemic inhibition of MTAP leading to increased MTA in blood, tumors, and urine.…”

Section: Discussionmentioning

confidence: 65%

“…Deletion of the MTAP gene often occurs together with p16 (CDKN2A, a tumor suppressor gene) and is common in human tumor-derived cell lines and in primary tumors (15). This co-deletion has led to speculation that MTAP is also a tumor suppressor (16,17). Although MTAP genetic knock-out in mice is embry- onic lethal (day 8), heterozygotes (MTAP ϩ/Ϫ ) are prone to age-related leukemia, also supporting the postulate that MTAP is a tumor suppressor gene (3).…”

Section: Discussionmentioning

confidence: 98%

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Growth and Metastases of Human Lung Cancer Are Inhibited in Mouse Xenografts by a Transition State Analogue of 5′-Methylthioadenosine Phosphorylase

Basu

Locker

Cassera

et al. 2011

Journal of Biological Chemistry

101

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The S-adenosylmethionine (AdoMet) salvage enzyme 5 -methylthioadenosine phosphorylase (MTAP) has been implicated as both a cancer target and a tumor suppressor. We tested these hypotheses in mouse xenografts of human lung cancers. AdoMet recycling from 5 -methylthioadenosine (MTA) was blocked by inhibition of MTAP with methylthioDADMe-Immucillin-A (MTDIA), an orally available, nontoxic, picomolar transition state analogue. Blood, urine, and tumor levels of MTA increased in response to MTDIA treatment. Disruption of pathways linked to polyamine synthesis and S-adenosylmethionine (AdoMet) 2 salvage provides metabolic targets in anticancer therapy based on the essential roles of these metabolites in cell growth. AdoMet is the major methyl donor for biosynthetic methylation reactions, a precursor for polyamine synthesis, and the source of methyl groups for DNA methylation. Targeting polyamine metabolism directly at L-ornithine decarboxylase by ␣,␣-difluoromethylornithine has had limited anticancer success (1). Two AdoMet molecules are converted to 5Ј-methylthioadenosine (MTA) in spermine synthesis, and 5Ј-methylthioadenosine phosphorylase (MTAP) recycles MTA by phosphorolysis to permit subsequent resynthesis of AdoMet (Fig. 1). Our working hypothesis was that inhibition of MTAP would affect cellular MTA and AdoMet metabolism with downstream effects on protein, DNA methylation, polyamine synthesis, and polyamine-dependent enzyme reactions. We targeted MTAP by transition state analysis and developed methylthio-DADMe-Immucillin-A (MTDIA), an orally available transition state analogue inhibitor of MTAP (2). Others have proposed that MTAP is a tumor suppressor gene (3), and experiments here explore the effects of MTAP inhibition in human lung cancer xenografts.We previously demonstrated that treatment of human FaDu head and neck tumors in mouse xenografts with MT-DIA prevented tumor growth with no apparent toxicity to the mice (4). Here, we report that both MTAP-positive (H358) and MTAP-deleted (A549) human lung cancer cell lines are also sensitive to MTAP inhibition in mouse xenografts. The mechanism is probed by the metabolic and genetic consequences of MTDIA administration. In culture, MTDIA in combination with MTA slows A549 cell growth but induces apoptosis in H358 cells.Lung cancer is the leading cause of cancer-related deaths worldwide (5). Patients diagnosed at an advanced stage have a median survival of less than 12 months (6 -8). Thus, development of novel therapeutics for lung cancer is a research priority. MTDIA demonstrated significant suppression of tumor growth with human lung cancer A549 and H358 cells in mouse xenografts. Low toxicity, oral availability, and significant tumor suppression by MTDIA all support additional evaluation as an agent for the treatment of lung cancers. EXPERIMENTAL PROCEDURESCell Lines-Human non-small cell lung adenocarcinoma (NSCLC) cell line A549 and prostate carcinoma cell line PC3 were obtained from the American Type Culture Collection (Manassas, VA). Human bronchioloalveolar ...

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 98%

Growth and Metastases of Human Lung Cancer Are Inhibited in Mouse Xenografts by a Transition State Analogue of 5′-Methylthioadenosine Phosphorylase

Basu

Locker

Cassera

et al. 2011

Journal of Biological Chemistry

101

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“…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%

“…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%

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

et al. 2016

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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.

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“…For example, MTA is converted to MTR-1P by methylthioadenosine phosphorylase (MTAP; EC 2.4.2.28). Continuous MTA metabolism is extremely important in mammals, as loss of MTAP activity is associated with cancer (Bertino et al, 2011) and accumulation of MTA has been linked to tumor progression (Stevens et al, 2009).…”

mentioning

confidence: 99%

Recycling of Methylthioadenosine Is Essential for Normal Vascular Development and Reproduction in Arabidopsis

et al. 2012

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5#-Methylthioadenosine (MTA) is the common by-product of polyamine (PA), nicotianamine (NA), and ethylene biosynthesis in Arabidopsis (Arabidopsis thaliana). The methylthiol moiety of MTA is salvaged by 5#-methylthioadenosine nucleosidase (MTN) in a reaction producing methylthioribose (MTR) and adenine. The MTN double mutant, mtn1-1mtn2-1, retains approximately 14% of the MTN enzyme activity present in the wild type and displays a pleiotropic phenotype that includes altered vasculature and impaired fertility. These abnormal traits were associated with increased MTA levels, altered PA profiles, and reduced NA content. Exogenous feeding of PAs partially recovered fertility, whereas NA supplementation improved fertility and also reversed interveinal chlorosis. The analysis of PA synthase crystal structures containing bound MTA suggests that the corresponding enzyme activities are sensitive to available MTA. Mutant plants that expressed either MTN or human methylthioadenosine phosphorylase (which metabolizes MTA without producing MTR) appeared wild type, proving that the abnormal traits of the mutant are due to MTA accumulation rather than reduced MTR. Based on our results, we propose that the key targets affected by increased MTA content are thermospermine synthase activity and spermidinedependent posttranslational modification of eukaryotic initiation factor 5A.

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Direct and tumor microenvironment mediated influences of 5′‐deoxy‐5′‐(methylthio)adenosine on tumor progression of malignant melanoma

Cited by 52 publications

References 32 publications

Growth and Metastases of Human Lung Cancer Are Inhibited in Mouse Xenografts by a Transition State Analogue of 5′-Methylthioadenosine Phosphorylase

Growth and Metastases of Human Lung Cancer Are Inhibited in Mouse Xenografts by a Transition State Analogue of 5′-Methylthioadenosine Phosphorylase

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

Recycling of Methylthioadenosine Is Essential for Normal Vascular Development and Reproduction in Arabidopsis

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