Decrease in expression or activity of cytosolic phospholipase A2alpha increases cyclooxygenase-1 action: A cross-talk between key enzymes in arachidonic acid pathway in prostate cancer cells.
The eicosanoid pathway is activated in many types of cancers including prostate. Eicosanoids are synthesized from intracellular arachidonic acid (AA), which is released from membrane glycerophospholipids mainly by the action of cytosolic phospholipase A(2)alpha (cPLA(2)alpha). Thus, targeting cPLA(2)alpha has been proposed as a treatment option. The aim of this study was to determine the effect of cPLA(2)alpha inhibition on cyclooxygenase (COX) expression and PGE(2) production. Inhibition of cPLA(2)alpha expression by siRNA or activity by Efipladib in prostate cancer cell lines (PC3 and LNCaP) led to an increase in COX-1 protein and PGE(2) levels in a dose-dependent manner from 24 to 72 h. The COX-2 response was less evident. Efipladib treatment increased COX-1 promoter transcriptional activity without changing the rate of COX-1 protein degradation. Treatment with Efipladib also led to a decrease in most LOX products (HETEs) as measured by LC/MS/MS. Replenishing 5- and 12-HETEs abolished Efipladib-induced COX-1 and PGE(2) levels. Decreasing 5- and 12-HETE production, as a result of treating cells with inhibitors MK886 and Baicalein, respectively, mimicked the effect of Efipladib on COX-1 and PGE(2) levels. Hence, the mechanism underlying the cPLA(2)alpha inhibition-induced COX-1 is likely due to a decrease in LOX products, which may exert a negative feedback on COX-1 gene expression in prostate cancer cells. Considering that PGE(2) is a potent promoter of cancer cell proliferation and survival, understanding the mechanism coupling cPLA(2)alpha with COX-1 is of potential clinical significance.
Central Clinical School, Department of Endocrinology and Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia.
Marzieh
M
Niknami
Soma
S
Vignarajan
Mu
M
Yao
Sheng
S
Hua
Paul K
PK
Witting
Yoshihiro
Y
Kita
Takao
T
Shimizu
Paul
P
Sved
Manish I
MI
Patel
Qihan
Q
Dong
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000096:biosynthesis; D016718:Arachidonic Acid / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000096:biosynthesis*; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D014158:Transcription, Genetic / Q000187:drug effects
D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D009363:Neoplasm Proteins; D016718:Arachidonic Acid; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D054513:Group IV Phospholipases A2; C516389:PLA2G4A protein, human; D015232:Dinoprostone