Decrease in expression or activity of cytosolic phospholipase A(2)alpha increases cyclooxygenase-1 action: A cross-talk between key enzymes in arachidonic acid pathway in prostate cancer cells

作者：Niknami Marzieh; Vignarajan Soma; Yao Mu; Hua Sheng; Witting Paul K; Kita Yoshihiro; Shimizu Takao; Sved Paul; Patel Manish I; Dong Qihan^*

来源：Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids, 2010, 1801(7): 731-737.

DOI：10.1016/j.bbalip.2010.03.003

• cPLA(2)-alpha
• Cyclooxygenase
• Lipoxygenase
• Prostate cancer

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 (PO 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-HETE5 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. 0 2010 Elsevier B.V.

• 出版日期2010-7