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

Abstract

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.

Correlation of tumor growth suppression and methionine aminopetidase-2 activity blockade using an orally active inhibitor

“…The antiproliferative activity of A-800141 was not limited to endothelial cells, as originally proposed for fumagillin and TNP-470 (16), but extended to many tumor cell lines as well, which is described in detail elsewhere (25). The antiproliferative activity of the sulfonamide series of inhibitors has been shown to correlate tightly with their cellular activity inhibiting MetAP2 enzyme function (21).…”

Natural product derivative Bis(4-fluorobenzyl)trisulfide inhibits tumor growth by modification of β-tubulin at Cys 12 and suppression of microtubule dynamics

“…The normalized CI is an arbitrary unit derived from electrical impedance measurement (19)(20)(21)(22). The correlation between CI and cell viability is well documented in the literature (23)(24)(25)(26). Furthermore, we also tested cell death and apoptosis in three selected tumor lines, A549, HT29, and SH-SY5Y, treated with 1 μmol/L BFBTS, the concentration approximating the IC 50 value for cell proliferation and cytotoxicity (Table 1).…”

METAP2 (methionyl aminopeptidase 2)

“…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.…”

“…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).…”