Methionine aminopeptidase-2 regulates human mesothelioma cell survival - Role of bcl-2 expression and telomerase activity

Methionine aminopeptidase-2 (MetAP2) is the molecular target of the angioge nesis inhibitors, famagillin and ovalacin. Fumagillin can also inhibit canc er cell proliferation, implying that MetAP2 may play a quite complex role i n tumor progression. Here, we examined the expression and function of MetAP 2 in an in vitro model of human mesothelioma. We found that mesothelioma ce lls expressed higher MetAP2 mRNA levels than primary normal mesothelial cel ls. Consistently, fumagillin induced apoptosis, owing to early mitochondria l damage, in malignant, but not in normal mesothelial cells. Transfection o f 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 a s well as telomerase activity were selectively reduced after MetAP2 inhibit ion in mesothelioma cells, whereas bcl-2 overexpression counteracted the ef fect of MetAP2 inhibition on telomerase activity and apoptosis. MetAP2 inhi bition also increased caspase activity and the caspase inhibitor, zVAD-fmk, prevented fumagillin-induced apoptosis, but it did not alter telomerase ac tivity. These results indicate that MetAP2 is a main regulator of prolifera tive and apoptotic pathways in mesothelioma cells and suggest that MetAP2 i nhibition may represent a potential target for therapeutic intervention in human mesothelioma.