12q22

MAP2,MNPEP,p67eIF2

Mesothelioma

Various reports suggested that MetAP2 plays an important role in the growth of different types of tumors. Malignant mesothelioma cells expressed higher MetAP2 mRNA levels compared to normal mesothelioma cells (Catalano et al., 2001). Transfection of mesothelioma cells with a MetAP2 anti-sense oligonucleotide revealed a time-dependent inhibition of cell survival and induced nucleosome formation. MetAP2 is a main regulator of the proliferative and apoptotic pathways in mesothelioma cells and MetAP2 inhibition may represent a potential target for therapeutic intervention in human mesothelioma (Catalano et al., 2001).

Lymphomas

A high level of MetAP2 was reported in malignant lymphomas exclusively in B-cell lymphoma subtypes (Kanno et al., 2002).

Colorectal adenocarcinoma

It has been reported that a high expression of MetAP2 in colorectal adenocarcinoma patients (Selvakumar et al., 2004a). Since myristoylation reaction is catalyzed by NMT, we reported that a cross-talk among the MetAP2, and NMT in HT29 cells (Selvakumar et al., 2004b). The expression of pp60c-src, MetAP2, and NMT was dependent on the cell density (Selvakumar et al., 2004b).

Esophageal squamous carcinoma

Microarray gene expression analysis of human esophageal squamous cell carcinomas revealed that MetAP2 was down-regulated when irradiated (Bo et al., 2004).

Hepatoma

Anti-sense of MetAP2 also induces apoptosis in rat hepatoma cells (Datta and Datta, 1999). A recent study suggested that fumagillin effectively inhibits both liver tumor growth and metastasis in rats in vivo (Sheen et al., 2005).

Neuroblastoma

The angiogenesis inhibitor TNP470, O-(chloro-acetyl-carbamoyl) fumagillol, a synthetic analogue of fumagillin, suppressed the expression of MetAP2 in human neuroblastoma and thus, MetAP2 may be an important molecular target for human neuroblastomas (Morowitz et al., 2005). The intracellular enzyme MetAP2 became such a candidate target enzyme due to its inactivation by the widely investigated anticancer agent TNP470 (Abe et al., 1994; Adams et al., 2004; Griffith et al., 1997; Hu et et al., 2006; Hu et al., 2007; Sin et al., 1997). Previously, inhibition of MetAP2 by TNP470 has been shown to activate p53 for cell-cycle arrest. In fact, the primary mouse embryonic fibroblasts were demonstrated to be sensitive to TNP470 and other MetAP2-specific inhibitors in a p53-dependent fashion. Several MetAP2 inhibitors were studied based on the inhibition of MetAP activity (Griffith et al., 1998; Antoine et al., 1994; Kusaka et al., 1994; Wang et al., 2000; Wang et al., 2003; Yeh et al., 2000; Zhang et al., 2000; Kim et al., 2004; Towbin et al., 2003).

Various cancer

MetAP2 inhibitors
It has been reported that MetAP2 could function as an oncogene (Tucker et al., 2008). Furthermore, various Src family tyrosine kinases, ADP ribosylation factors and eukaryotic transcription elongation factor-2 were substrates of MetAP2 which plays a significant role in the progression of metastasis (Tucker et al., 2008). A derivative of the natural product fumagillin, TNP470 has been shown to be safe and effective in the treatment of solid tumors in several animal studies and preclinical trials. TNP470 entered human clinical trials for the treatment of AIDS-related Kaposis sarcoma, metastatic breast cancer, androgen-independent prostate cancer, pediatric solid tumors, lymphomas, acute leukemia, advanced squamous cell cancer of the cervix, and metastatic renal carcinoma (Dezube et al., 1998; Kruger and Figg, 2000; Kudelka et al., 1997). Several MetAP2 inhibitors were studied based on the inhibition of MetAP activity (Griffith et al., 1998; Antoine et al., 1994; Kusaka et al., 1994; Wang et al., 2000; Yeh et al., 2000; Zhang et al., 2000; Kim et al., 2004). Previously, inhibition of MetAP2 by TNP470 has been shown to activate p53 for cell-cycle arrest (Yeh et al., 2000; Zhang et al., 2000).
The Src family kinases have been shown to play pivotal roles in cell-cycle progression, making them potential candidates to mediate the cell-cycle effects of MetAP inhibitors. MetAP2 plays a critical role in the proliferation of endothelial cells and certain tumor cells and thus serves as a promising target for anti-angiogenesis and anti-cancer drugs (Bo et al., 2004). The inhibition of MetAP2 expression in mesothelioma cells leads to cell death and that such apoptosis is avoided in cases where there is overexpression of Bcl-2 (Catalano et al., 2001). The upregulation of Bcl-2 in colorectal cancer is well established by various investigators (Rajala et al., 2000; Yu et al., 2003; Valassiadou et al., 1997).