Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.736
5-Year Impact Factor – 2.135
Index Copernicus  – 168.52
MEiN – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

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Advances in Clinical and Experimental Medicine

2016, vol. 25, nr 1, January-February, p. 117–128

doi: 10.17219/acem/60715

Publication type: original article

Language: English

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

Hajime Shimizu1,2,A,B,C,D,F, Shigeki Yamagishi3,B,C,E, Hideki Chiba2,E,F, Mohammad Ghazizadeh1,A,C,D,E,F

1 Department of Molecular Pathology, Institute of Gerontology, Nippon Medical School, Japan

2 Department of Basic Pathology, Fukushima Medical University, Fukushima, Japan

3 Department of Surgery, Division of Thoracic Surgery, Aizu Chuo Hospital, Fukushima, Japan

Abstract

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).
Conclusion. 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.

Key words

apoptosis, methionine aminopeptidase 2 (MetAP2), myristoylation, fumagillin, non-small-cell lung cancer (NSCLC)

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