Regulation of PSA secretion and survival signaling by calcium-independent phopholipase A(2)beta in prostate cancer cells.
BACKGROUND
Serum prostate specific antigen (PSA) levels in prostate cancer patients serve as a useful biomarker for diagnosing and monitoring prostate cancer. Recently, secreted PSA has been characterized as an autocrine survival factor through activation of Akt and induction of AR. In the normal prostate, PSA is secreted in the lumen of prostatic ducts to lyse proteins in the seminal coagulum.


METHODS
However, the mechanism for constitutive PSA secretion from benign prostate and its transport across the prostate-blood barrier into serum are unknown. Regulation of peptide secretion by iPLA(2)-beta has been reported in non-prostatic tissue and in prostate tissue iPLA(2)-beta is reported to be under androgen regulation. We investigated whether iPLA(2) plays a role for in PSA secretion by comparing iPLA(2) activity and expression in normal prostate epithelial RWPE-1 cells and in LNCaP prostate cancer cells. Expression of the two active iPLA(2)-beta mRNA splice variants, LH-iPLA(2) and SH-iPLA(2), were increased and the inhibitory ankyrin-iPLA(2) isoform was markedly reduced in LNCaP cells as compared to normal prostate epithelial RWPE-1 cells.


RESULTS
These changes are consistent with a higher enzymatic activity in LNCaP cells. The iPLA(2)-beta-specific inhibitor BEL inhibited PSA secretion and induced apoptosis in LNCaP cells. iPLA(2) knockdown using SiRNA inhibited PSA secretion, downregulated AR and induced apoptosis. Exogenous PSA suppressed BEL-induced apoptosis and neutralizing anti-PSA antibody blocked the survival effect of PSA.


CONCLUSIONS
These data indicate that iPLA(2)-beta participates in regulating PSA secretion and supports the concept that secreted PSA provides an autocrine survival function in LNCaP cells.
Nicotera
Thomas M
TM
Department of Cancer Prevention & Population Sciences, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. thomas.nicotera@verizon.net
Schuster
David P
DP
Bourhim
Mustapha
M
Chadha
Kailash
K
Klaich
Gary
G
Corral
David A
DA
D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011467:Prostate / Q000166:cytology; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D020033:Protein Isoforms; D011753:Pyrones / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015996:Survival Rate
D007527:Isoenzymes; D009281:Naphthalenes; D010726:Phosphodiesterase Inhibitors; D020033:Protein Isoforms; D011753:Pyrones; D012333:RNA, Messenger; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; D054513:Group IV Phospholipases A2; D017430:Prostate-Specific Antigen; D002118:Calcium