Microsomal prostaglandin E synthase 1 determines tumor growth in vivo of prostate and lung cancer cells

There is strong evidence for a role of prostaglandin E-2 (PGE(2)) in cancer cell proliferation and tumor development. In PGE(2) biosynthesis, cyclooxygenases (COX-1/COX-2) convert arachidonic acid to PGH(2), which can be isomerized to PGE(2) by microsomal PGE-synthase-1 (MPGES-1). The human prostate cancer cell line DU145 expressed high amounts of MPGES-1 in a constitutive manner. MPGES-1 expression also was detectable in human prostate cancer tissues, where it appeared more abundant compared with benign hyperplasia. By using shRNA, we established stable and practically complete knockdown of MPGES-1, both in DU145 cells with high constitutive expression and in the non-small cell lung cancer cell line A549, where MPGES-1 is inducible. For microsomes prepared from knockdown clones, conversion of PGH(2) to PGE(2) was reduced by 85-90%. This resulted in clear phenotypic changes: MPGES-1 knockdown conferred decreased clonogenic capacity and slower growth of xenograft tumors (with disintegrated tissue structure) in nude mice. For DU145 cells, MPGES-1 knockdown gave increased apoptosis in response to genotoxic stress (adriamycin), which could be rescued by exogenous PGE(2). The results suggest that MPGES-1 is an alternative therapeutic target in cancer cells expressing this enzyme.