Methionine Aminopeptidase 2 as a Potential Therapeutic Target for Human Non-Small-Cell Lung Cancers.

BACKGROUND:Methionine aminopeptidase 2 (MetAP2) is a bi-functional protein that plays a critical role in the regulation of post-translational processing and protein synthesis. OBJECTIVES:We studied whether MetAP2 is activated and expressed in human non-small-cell lung cancer (NSCLC) tissues and whether inactivation of MetAP2 activity, with its specific inhibitor fumagillin, potentially inhibits proliferation of NSCLC cells. MATERIAL AND METHODS:The expression and function of MetAP2 were evaluated in NSCLC tissues, primary cell cultures and cell lines using immunohistochemistry, RT-PCR, Western blot, aminopeptidase activity assay and flow cytometry. MetAP2 expression was also studied in relation to clinicopathological factors. RESULTS:MetAP2 expression in NSCLS, including adenocarcinoma (ADC) and squamous cell carcinoma (SCC), showed a moderate to strong positive reaction while normal appearing bronchial epithelium showed weak staining and normal alveolar epithelial cells were widely negative. A high MetAP2 mRNA and protein expression was found in NSCLC tissues. The aminopeptidase activity in NSCLC was 2-fold higher than that in normal lung tissues. In a series of 41 ADC patients, MetAP2 expression was significantly correlated with patient's outcome or survival time. Inhibition of MetAP2 by fumagillin in SCC cell lines revealed a significant increase in caspase-3 activity as compared to the control (p = 0.001). CONCLUSIONS:Our results indicate that MetAP2 is involved in NSCLC and is an important regulator of proliferative and apoptotic targets. Thus inhibition of MetAP2, such as by fumagillin, may be a potential therapeutic modality for prevention of tumor cell growth, development and progression in NSCLC patients.

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