Characterization of Methylthioadenosin Phosphorylase (MTAP) Expression in Malignant Melanoma

Behrmann, Iris; Wallner, Susanne; Komyod, Waraporn; Heinrich, Peter C.; Schuierer, Marion; Buettner, Reinhard; Bosserhoff, Anja‐Katrin

doi:10.1016/s0002-9440(10)63695-4

Cited by 122 publications

(148 citation statements)

References 16 publications

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“…Primary human melanocytes and total human liver tissue served as control, since both had been shown previously to express high levels of MTAP. 21 In contrast to several other tumours reported, strong expression of MTAP mRNA was found in five out of six analysed colon carcinoma cell lines comparable to the expression levels in primary human melanocytes and total human liver tissue, respectively (Figure 1a). Only the colon carcinoma cell line SW480 showed relatively weak expression of MTAP.…”

Section: Expression Of Mtap In Colon Carcinoma Cell Lines and Primarymentioning

confidence: 47%

“…Since it has been shown previously that the expression of MTAP is reduced or totally lost in several tumours compared to the normal tissue, 2-5, 21 we analysed MTAP mRNA expression in six colon carcinoma cell lines in comparison to primary human CEC using quantitative PCR. Primary human melanocytes and total human liver tissue served as control, since both had been shown previously to express high levels of MTAP.…”

Section: Expression Of Mtap In Colon Carcinoma Cell Lines and Primarymentioning

confidence: 99%

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Strong expression of methylthioadenosine phosphorylase (MTAP) in human colon carcinoma cells is regulated by TCF1/[beta]-catenin

Bataille

Rogler

Modes

et al. 2005

Laboratory Investigation

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Methylthioadenosine phosphorylase (MTAP) is known as a ubiquitously expressed house keeping gene important in biochemical salvage processes. The MTAP gene is localized on the human chromosomal region 9p21, a region often deleted in cancer. Recently, several groups including our own have shown that MTAP serves as a tumour suppressor gene. The aim of this study was to analyse the role of MTAP in colon carcinoma and normal colon epithelium and the regulation of gene expression. To examine MTAP RNA and protein expression, we screened six colon carcinoma cell lines and human primary colon epithelial cells by RT-PCR and immunoblotting. MTAP expression was confirmed in vivo by immunohistochemical staining of normal colon tissue compared to adenoma and colon carcinoma. Interestingly, we found strong MTAP mRNA and protein expression by colon carcinoma cell lines but no expression by colonic epithelial cells. To analyse the regulation of MTAP expression, promoter studies were performed and revealed control of MTAP expression by LEF/TCF/bcatenin. Furthermore, we demonstrated a significant correlation between MTAP protein expression and tumour progression as the intensity of MTAP protein staining increased from normal tissue to carcinoma. In addition, the recently postulated association between MTAP activity and interferon (IFN) sensitivity was confirmed in colon epithelial cells showing only little response to IFN-gamma, in contrast to the carcinoma cell lines. In summary, these data indicate for the first time that MTAP is not expressed in normal human colonic epithelium but is strongly upregulated in colon carcinoma. This finding may be of clinical significance concerning the homeostasis of normal colon epithelium and potential treatment of colon carcinoma. Laboratory Investigation ( 2.28) plays a major role in polyamine metabolism and is important for the salvage of both adenine and methionine. MTAP catalyses the phosphorylation of methylthioadenosine (MTA), a by-product of the synthesis of polyamines, which acts as a potent inhibitor of polyamine aminopropyltransferase and methyltransferases. MTAP has been shown previously to be expressed abundantly in normal cells and tissues. 1 In contrast, many malignant cells lack MTAP activity, 2-5 and cultured MTAP-deficient cells secrete MTA instead of metabolising it. 6 The reason for the frequent loss of MTAP activity became evident after determining the chromosomal location of MTAP. Starting from the centromeric end, the gene order on human chromosome 9p21 was mapped as p15-p16-MTAP-interferon(IFN)-alpha-IFNbeta. 1 In this region, many tumours reveal selective deletions. Recently, MTAP gene deletions were described in endometrial cancer, osteosarcoma and in haematological neoplasias like lymphoblastic leukaemia or non-Hodgkin's lymphomas. [2][3][4][5] In addition to its role in polyamine metabolism, MTAP expression has recently been shown to have significant impact on signal transducer and activator of transcription (STAT) 1 activity. 7 STAT1 is

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Section: Expression Of Mtap In Colon Carcinoma Cell Lines and Primarymentioning

confidence: 47%

Section: Expression Of Mtap In Colon Carcinoma Cell Lines and Primarymentioning

confidence: 99%

Strong expression of methylthioadenosine phosphorylase (MTAP) in human colon carcinoma cells is regulated by TCF1/[beta]-catenin

Bataille

Rogler

Modes

et al. 2005

Laboratory Investigation

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“…5-azacytosine treatment for analysis of promoter methylation was performed as previously described (Behrmann et al, 2003).…”

Section: Cell Culturementioning

confidence: 99%

Expression of Dickkopf genes is strongly reduced in malignant melanoma

et al. 2006

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The Dickkopf (DKK) genes were originally identified as factors inducing head formation in Xenopus. The genes code for inhibitors that are involved in Wnt signaling. We speculate that loss of DKK expression plays a role in development or progression of malignant melanoma. Thus, we evaluated melanoma cell lines and tissue samples of malignant melanoma for loss of DKK, especially DKK-3 transcription. We found that DKK-1, -2 and -3 were downregulated or lost in all cell lines and in most of the tumor samples analysed. Reduced DKK-3 expression occurred as early as in primary tumors detected by both immunohistochemical and reverse transcription-polymerase chain reaction RT-PCR analysis. Functional assays with stable DKK-3 transfected cell lines revealed that DKK-3 expression increased cell-cell adhesion and decreased cell migration. Further, downregulation of fibronectin, snail-1 and re-expression of E-cadherin was found in the DKK-3 expressing cell clones supporting a role of DKK-3 in tumor progression. Our studies thus indicate that loss of DKK-3 expression may contribute to melanoma progression.

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“…MTAP deletions have been shown in a wide variety of cancers including T cell acute lymphoblastic leukemia (22), pancreatic cancer (23), osteosarcoma (24), biliary tract cancers (11), gliomas (25), and melanoma (14). More relevant to pemetrexed, MTAP is deleted in f70% of pleural mesotheliomas (4) and in f38% of non -small cell lung cancers (26).…”

Section: Discussionmentioning

confidence: 99%

“…This cDNA was diluted 1:8 and used for quantitative realtime PCR using the ABI 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA) and Sybr Green for product quantitation. The MTAP primers used were reported previously (14) and named MTAP for2 (5 ¶-GCG AAC ATC TGG GCT TTG-3 ¶) and MTAP rev2 (5 ¶-GCA CCG GAG TCC TAG CTT C-3 ¶). h-Actin was used to normalize MTAP expression using previously reported primers (15): sense primer, 5 ¶-CGTGCTGCTGACCGAGC-3 ¶ and antisense primer, 5 ¶-GAAGGTCTCAAACATGATC-TGGGT-3 ¶.…”

Section: Chemicals and Cell Linesmentioning

confidence: 99%

The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on pemetrexed activity

Chattopadhyay¹,

Zhao²,

Tsai³

et al. 2006

Molecular Cancer Therapeutics

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Pemetrexed is a new-generation antifolate inhibitor of thymidylate synthase (TS) and a weaker inhibitor of glycinamide ribonucleotide transformylase (GARFT) required for de novo purine synthesis. Methylthioadenosine phosphorylase (MTAP) salvages purines by releasing adenine from methylthioadenosine and is often deleted in mesothelioma. The current study addresses the effect of MTAP on pemetrexed activity using a highly potent transition state inhibitor of MTAP, MT-DADMe-Immucillin A (ImmA; K i = 86 pmol/L) in the MTAP(+) NCI-H28 and MTAP(À) NCI-H2052 mesothelioma cell lines. Based on selective nucleoside protection, TS was found to be the primary pemetrexed target in both cell lines with GARFT inhibition requiring 20-to 30-fold higher pemetrexed concentrations. ImmA had no effect on pemetrexed activity but, when thymidine was added, the pemetrexed IC 50 decreased by a factor of f3 in MTAP(+) H28 cells with no effect in MTAP(À) H2052 cells. Conversely, the transfection of MTAP into H2052 cells increased the pemetrexed IC 50 by nearly 3-fold but only in the presence of thymidine; this was reversed by ImmA. An MTAPspecific short interfering RNA produced a 2-fold decrease in pemetrexed IC 50 in MTAP(+) HeLa cells in the presence of thymidine. These data indicate that suppression of constitutive MTAP has no effect on pemetrexed activity when the primary target is TS. There is a modest salutary effect when the pemetrexed target is GARFT alone. [Mol Cancer Ther 2006;5(10):2549 -55]

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Characterization of Methylthioadenosin Phosphorylase (MTAP) Expression in Malignant Melanoma

Cited by 122 publications

References 16 publications

Strong expression of methylthioadenosine phosphorylase (MTAP) in human colon carcinoma cells is regulated by TCF1/[beta]-catenin

Strong expression of methylthioadenosine phosphorylase (MTAP) in human colon carcinoma cells is regulated by TCF1/[beta]-catenin

Expression of Dickkopf genes is strongly reduced in malignant melanoma

The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on pemetrexed activity

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