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


ABSTRACT: 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.

SUBMITTER: Hanaka H 

PROVIDER: S-EPMC2768589 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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

Hanaka Hiromi H   Pawelzik Sven-Christian SC   Johnsen John Inge JI   Rakonjac Marija M   Terawaki Kan K   Rasmuson Agnes A   Sveinbjörnsson Baldur B   Schumacher Martin C MC   Hamberg Mats M   Samuelsson Bengt B   Jakobsson Per-Johan PJ   Kogner Per P   Rådmark Olof O  

Proceedings of the National Academy of Sciences of the United States of America 20091021 44


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 w  ...[more]

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