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.
Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Hiromi
H
Hanaka
Sven-Christian
SC
Pawelzik
John Inge
JI
Johnsen
Marija
M
Rakonjac
Kan
K
Terawaki
Agnes
A
Rasmuson
Baldur
B
Sveinbjörnsson
Martin C
MC
Schumacher
Mats
M
Hamberg
Bengt
B
Samuelsson
Per-Johan
PJ
Jakobsson
Per
P
Kogner
Olof
O
Rådmark
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D000071876:Prostaglandin-E Synthases; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D021381:Protein Transport / Q000187:drug effects; D011944:Receptors, Androgen / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
D011944:Receptors, Androgen; D004317:Doxorubicin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse