期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 44, 页码 18757-18762出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0910218106
关键词
arachidonic acid; cyclooxygenase; eicosanoid; prostaglandin E2
资金
- Swedish Research Council
- European Union [LSHM-CT-2004-00533, FP7-Health-201668]
- Swedish Children's Cancer Foundation
- Stockholm Cancer Society
- Swedish Cancer Foundation
- Nakatomi Foundation
- Naito Foundation
- Scandinavia-Japan Sasakawa Foundation
- Nakayama Foundation for Human Science
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.
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