Methionine aminopeptidase 2 over-expressed in cholangiocarcinoma: potential for drug target.
Methionine aminopeptidases (MetAP) are proteases which remove the N-terminal methionine from newly synthesized proteins. Associations of MetAP2 with tumor progression of different cancers have been repeatedly reported. We aim to determine if MetAP2 is expressed in cholangiocarcinomas (CCA) and investigate to see if it would be a useful therapeutic target. We evaluated MetAP2 expression by immunohistochemistry in 82 patients of intrahepatic CCA. MetAP2 was expressed in bile ducts to various degrees. It was occasionally expressed with weak staining in normal bile duct epithelium but was strikingly over-expressed in dysplastic bile duct epithelia, primary and metastatic CCA tissues (p < 0.001). The increased expression of MetAP2 in proliferating bile duct was evident. All metastatic tumors had stronger expression of MetAP2 than the corresponding primary tumors. Fumagillin, a MetAP2 specific inhibitor, significantly inhibited cell proliferation in dose dependent manner and the degree of growth inhibition was dependent on the amount of cellular enzyme. The present study highlights the involvement of MetAP2 in an early event of carcinogenesis of CCA. The findings represent the first description of increased MetAP2 expression in CCA. The inhibition of enzyme activity using MetAP2 inhibitors may be a potential strategy for long-term control of tumor development and progression in CCA patients.
Sawanyawisuth
Kanlayanee
K
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
Wongkham
Chaisiri
C
Pairojkul
Chawalit
C
Saeseow
O-Tur
OT
Riggins
Gregory J
GJ
Araki
Norie
N
Wongkham
Sopit
S
D000328:Adult; D000368:Aged; D000626:Aminopeptidases / Q000096:biosynthesis* / Q000187:drug effects*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000097:blood; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D003510:Cyclohexanes / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D004848:Epithelium / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000187:drug effects*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D012717:Sesquiterpenes / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D012717:Sesquiterpenes; C026211:fumagillin; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases