Oncogenic action of phospholipase A2 in prostate cancer.
Mortality from prostate cancer is a result of progression of cancer cells to become androgen-refractory and metastatic. Eicosanoid products of the cyclooxygenase (COX) and lipoxygenase (LOX) pathways are important mediators of the proliferation of prostate cancer cells in culture and regulate tumour vascularisation and metastasis in animal models. Pharmacological agents that block either COX or LOX products effectively reduce the size of prostate cancer xenografts. Recently, phospholipase A(2) (PLA(2)) enzymes, which regulate the provision of arachidonic acid to both COX- and LOX-derived eicosanoids, are found to also regulate the growth of prostate cancer cells and tumours, with one enzyme, secreted PLA(2)-IIA, being increased in prostate cancer tissues. Annexin A1 and A2, known inhibitors of cytosolic phospholipase A(2)-alpha activity, are absent in prostate cancer tissues. We propose that PLA(2) enzyme function is dysregulated by aberrant up regulation of secreted enzymes and downregulation of endogenous inhibitors of cytosolic phospholipase A(2) activity in prostate cancer and that this dysregulation contributes to the pathogenesis of prostate cancer. Thus, in addition to COX and LOX enzymes, PLA(2) enzymes represent important targets for the treatment of prostate cancer.
Dong
Qihan
Q
Department of Medicine, the University of Sydney, NSW 2006, Australia. qhd@med.usyd.edu.au
Patel
Manish
M
Scott
Kieran F
KF
Graham
Garry G
GG
Russell
Pamela J
PJ
Sved
Paul
P
D000728:Androgens / Q000494:pharmacology; D000818:Animals; D017305:Annexin A1 / Q000378:metabolism; D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D015777:Eicosanoids / Q000096:biosynthesis / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D054501:Group II Phospholipases A2; D054513:Group IV Phospholipases A2; D006801:Humans; D008297:Male; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D054467:Phospholipases A2; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000728:Androgens; D017305:Annexin A1; D017306:Annexin A2; D000970:Antineoplastic Agents; D015777:Eicosanoids; D004791:Enzyme Inhibitors; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054513:Group IV Phospholipases A2; D054467:Phospholipases A2