title: Methionine Aminopeptidase 2 as a Potential Therapeutic Target for Human Non-Small-Cell Lung Cancers.
abstract: Methionine aminopeptidase 2 (MetAP2) is a bi-functional protein that plays a critical role in the regulation of post-translational processing and protein synthesis.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Department of Molecular Pathology, Institute of Gerontology, Nippon Medical School, Japan; Department of Basic Pathology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Department of Surgery, Division of Thoracic Surgery, Aizu Chuo Hospital, Fukushima, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Yamagishi
authors.affiliation: Department of Basic Pathology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Chiba
authors.affiliation: Department of Molecular Pathology, Institute of Gerontology, Nippon Medical School, Japan.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ghazizadeh
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000369:Aged, 80 and over; D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003510:Cyclohexanes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D063208:Methionyl Aminopeptidases; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006023:Glycoproteins; D012717:Sesquiterpenes; C026211:fumagillin; D000626:Aminopeptidases; C081311:METAP2 protein, human; D063208:Methionyl Aminopeptidases