Abstract
Methionine aminopeptidase-2 (MetAP2) is the molecular target of the angiogenesis inhibitors, fumagillin and ovalacin. Fumagillin can also inhibit cancer cell proliferation, implying that MetAP2 may play a quite complex role in tumor progression. Here, we examined the expression and function of MetAP2 in an in vitro model of human mesothelioma. We found that mesothelioma cells expressed higher MetAP2 mRNA levels than primary normal mesothelial cells. Consistently, fumagillin induced apoptosis, owing to early mitochondrial damage, in malignant, but not in normal mesothelial cells. Transfection of mesothelioma cells with a MetAP2 anti-sense oligonucleotide determined a time-dependent inhibition of cell survival and induced nucleosome formation. Interestingly, mRNA and protein levels of the anti-apoptotic gene bcl-2 as well as telomerase activity were selectively reduced after MetAP2 inhibition in mesothelioma cells, whereas bcl-2 overexpression counteracted the effect of MetAP2 inhibition on telomerase activity and apoptosis. MetAP2 inhibition also increased caspase activity and the caspase inhibitor, zVAD-fmk, prevented fumagillin-induced apoptosis, but it did not alter telomerase activity. These results indicate that MetAP2 is a main regulator of proliferative and apoptotic pathways in mesothelioma cells and suggest that MetAP2 inhibition may represent a potential target for therapeutic intervention in human mesothelioma.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Chloromethyl Ketones / pharmacology
-
Aminopeptidases / genetics*
-
Aminopeptidases / metabolism*
-
Angiogenesis Inhibitors / pharmacology*
-
Apoptosis / drug effects
-
Apoptosis / physiology*
-
Caspase 3
-
Caspases / metabolism
-
Cell Division / drug effects
-
Cell Survival / drug effects
-
Cell Survival / physiology
-
Collagen / pharmacology
-
Cyclohexanes
-
Cysteine Proteinase Inhibitors / pharmacology
-
Endostatins
-
Fatty Acids, Unsaturated / pharmacology
-
Genes, bcl-2
-
Humans
-
Mesothelioma / enzymology*
-
Mesothelioma / genetics
-
Mesothelioma / pathology*
-
Metalloendopeptidases / genetics*
-
Metalloendopeptidases / metabolism*
-
Oligodeoxyribonucleotides, Antisense / pharmacology
-
Peptide Fragments / pharmacology
-
Proto-Oncogene Proteins c-bcl-2 / genetics
-
Proto-Oncogene Proteins c-bcl-2 / metabolism*
-
RNA, Messenger / genetics
-
Sesquiterpenes
-
Suramin / pharmacology
-
Telomerase / metabolism*
-
Thalidomide / pharmacology
-
Transcription, Genetic
-
Transfection
-
Tumor Cells, Cultured
Substances
-
Amino Acid Chloromethyl Ketones
-
Angiogenesis Inhibitors
-
Cyclohexanes
-
Cysteine Proteinase Inhibitors
-
Endostatins
-
Fatty Acids, Unsaturated
-
Oligodeoxyribonucleotides, Antisense
-
Peptide Fragments
-
Proto-Oncogene Proteins c-bcl-2
-
RNA, Messenger
-
Sesquiterpenes
-
benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
-
Thalidomide
-
Suramin
-
fumagillin
-
Collagen
-
Telomerase
-
Aminopeptidases
-
methionine aminopeptidase 2
-
CASP3 protein, human
-
Caspase 3
-
Caspases
-
Metalloendopeptidases