High Expression of Methionine Aminopeptidase 2 in Human Colorectal Adenocarcinomas

Selvakumar, Ponniah; Lakshmikuttyamma, Ashakumary; Kanthan, Rani; Kanthan, Selliah; Dimmock, Jonathan R.; Sharma, Rajendra K.

doi:10.1158/1078-0432.ccr-03-0218

Cited by 47 publications

(23 citation statements)

References 36 publications

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“…High expression was also found in follicular lymphomas, 50% of the large B-cell lymphomas and all of the Burkitt's lymphomas examined. Elevated expression of MetAP2 was reported in human colorectal adenocarcinomas (Selvakumar et al, 2004).…”

Section: Discussionmentioning

confidence: 98%

“…MetAP2 is also found in higher concentrations in tumor cells compared with normal cells (Wu et al, 1993;Kanno et al, 2002). Furthermore, MetAP2 has been found to be overexpressed in colon cancers and is associated with metastatic disease progression (Selvakumar et al, 2004). When cultured mammalian cells are starved, the protein level of MetAP2 is reduced significantly; during mitogenic stimulation, cellular MetAP2 protein was rapidly induced (Wu et al, 1993;Wang et al, 2000;Kanno et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Ectopic expression of methionine aminopeptidase-2 causes cell transformation and stimulates proliferation

et al. 2008

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Methionine aminopeptidase-2 (MetAP2) processes N-terminal methionine from nascent cellular proteins. Inhibition of MetAP2 has been shown to block angiogenesis and suppress tumor growth in preclinical tumor models. However, the biological role of MetAP2 in cancer is not well understood. We examined the effect of three distinct chemical classes of MetAP2 inhibitors on the growth of a panel of human cancer cells in vitro. All MetAP2 inhibitors caused inhibition of tumor cell growth in both anchorage-dependent and, particularly, in anchorage-independent manner. These data prompted us to examine the possible roles of MetAP2 in cancers. Ectopic expression of MetAP2 in NIH-3T3 cells caused transformation, evidenced by the formation of foci in monolayer culture and growth of large colonies in soft agar. Overexpression of MetAP2 in an immortalized bronchial epithelial cell line NL20 accelerated growth. These phenotypes induced by the overexpression of MetAP2 were reversed by the treatment with MetAP2 inhibitors, indicating that the catalytic function of MetAP2 was essential. Accordingly, overexpression of a catalytically inactive MetAP2 resulted in growth retardation of HT1080 tumor cells, suggesting a dominant-negative role of the inactive MetAP2 mutant. Finally, we analysed the expression of MetAP2 in patient cancer samples by immunohistochemistry. Moderate-to-high staining was identified in the majority of breast, colon, lung, ovarian and prostate carcinomas examined. These data suggest that MetAP2 plays an important role in tumor cell growth and may contribute to tumorigenesis.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Ectopic expression of methionine aminopeptidase-2 causes cell transformation and stimulates proliferation

et al. 2008

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“…These results show that MetAP2 expression is observed in the Nf1À/À astrocytes prior to tumor formation in vivo, but the levels of MetAP2 expression increase as the tumors develop. Whereas increased MetAP2 expression has been reported in malignant cancers (26), this is the first report of increased MetAP2 expression in a benign neoplasm.…”

Section: Resultsmentioning

confidence: 56%

Cerebrospinal Fluid Proteomic Analysis Reveals Dysregulation of Methionine Aminopeptidase-2 Expression in Human and Mouse Neurofibromatosis 1–Associated Glioma

Dasgupta

Perry

et al. 2005

Cancer Research

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Individuals affected with the neurofibromatosis 1 (NF1) tumor predisposition syndrome are prone to the development of multiple nervous system tumors, including optic pathway gliomas (OPG). The NF1 tumor suppressor gene product, neurofibromin, functions as a Ras GTPase-activating protein, and has been proposed to regulate cell growth by inhibiting Ras activity. Recent studies from our laboratory have shown that neurofibromin also regulates the mammalian target of rapamycin activity in a Ras-dependent fashion, and that the rapamycin-mediated mammalian target of rapamycin inhibition ameliorates the Nf1À/À astrocyte growth advantage. Moreover, Nf1-deficient astrocytes exhibit increased protein translation. As part of a larger effort to identify protein markers for NF1-associated astrocytomas that could be exploited for therapeutic drug design, we did an objective proteomic analysis of the cerebrospinal fluid from genetically engineered Nf1 mice with optic glioma. One of the proteins found to be increased in the cerebrospinal fluid of OPGbearing mice was the eukaryotic initiation factor-2A binding protein, methionine aminopeptidase 2 (MetAP2). In this study, we show that Nf1 mouse OPGs and NF1-associated human astrocytic tumors, but not sporadic pilocytic or other lowgrade astrocytomas, specifically expressed high levels of MetAP2. In addition, we show that Nf1-deficient astrocytes overexpress MetAP2 in vitro and in vivo, and that treatment with the MetAP2 inhibitor fumagillin significantly reduces Nf1À/À astrocyte proliferation in vitro. These observations suggest that MetAP2 is regulated by neurofibromin, and that MetAP2 inhibitors could be potentially employed to treat NF1-associated tumor proliferation. (Cancer Res 2005; 65(21): 9843-50)

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“…MetAP2 expression is up-regulated in various human cancers, including mesothelioma, 40 B-cell lymphomas, 41 colorectal adenocarcinoma, 42 neurofibromatosis 1-associated human astrocytic tumor, 43 as well as cholangiocarcinoma, 44 and modulation of MetAP2 activity could present a target for therapeutic intervention. [45][46][47] The zebrafish model offers a unique opportunity in which the effects of metap2 modulation on hematopoietic and endothelial cells can be simultaneously examined and its high-throughput nature can enable pharmacologic screening for the rapid identification of therapeutic agents.…”

Section: Discussionmentioning

confidence: 99%

Methionine aminopeptidase 2 is required for HSC initiation and proliferation

Alvin¹,

Fung²,

Lin³

et al. 2011

Blood

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In a chemical screening, we tested the antiangiogenic effects of fumagillin derivatives and identified fumagillin as an inhibitor of definitive hematopoiesis in zebrafish embryos. Fumagillin is known to target methionine aminopeptidase II (MetAP2), an enzyme whose function in hematopoiesis is unknown. We investigated the role of MetAP2 in hematopoiesis by using zebrafish embryo and human umbilical cord blood models. Zebrafish metap2 was expressed ubiquitously during early embryogenesis and later in the somitic region, the caudal hematopoietic tissue, and pronephric duct. metap2 was inhibited by morpholino and fumagillin treatment, resulting in increased mpo expression at 18 hours postfertilization and reduced c-myb expression along the ventral wall of dorsal aorta at 36 hours postfertilization. It also disrupted intersegmental vessels in Tg-(fli1:gfp) embryos without affecting development of major axial vasculatures. Inhibition of MetAP2 in CB CD34 ؉ cells by fumagillin had no effect on overall clonogenic activity but significantly reduced their engraftment into immunodeficient nonobese diabetes/severe combined immunodeficiency mice.

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High Expression of Methionine Aminopeptidase 2 in Human Colorectal Adenocarcinomas

Cited by 47 publications

References 36 publications

Ectopic expression of methionine aminopeptidase-2 causes cell transformation and stimulates proliferation

Ectopic expression of methionine aminopeptidase-2 causes cell transformation and stimulates proliferation

Cerebrospinal Fluid Proteomic Analysis Reveals Dysregulation of Methionine Aminopeptidase-2 Expression in Human and Mouse Neurofibromatosis 1–Associated Glioma

Methionine aminopeptidase 2 is required for HSC initiation and proliferation

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