Cytosolic phospholipase A2-alpha: a potential therapeutic target for prostate cancer.
OBJECTIVE
Cytosolic phospholipase A2-alpha (cPLA2-alpha) provides intracellular arachidonic acid to supply both cyclooxygenase and lipoxygenase pathways. We aim to determine the expression and activation of cPLA2-alpha in prostate cancer cell lines and tissue and the effect of targeting cPLA2-alpha in vitro and in vivo.


METHODS
The expression of cPLA2-alpha was determined in prostate cancer cells by reverse transcription-PCR, Western blot, and immunocytochemistry. Growth inhibition, apoptosis, and cPLA2-alpha activity were determined after inhibition with cPLA2-alpha small interfering RNA or inhibitor (Wyeth-1). Cytosolic PLA2-alpha inhibitor or vehicle was also administered to prostate cancer xenograft mouse models. Finally, the expression of phosphorylated cPLA2-alpha was determined by immunohistochemistry in human normal, androgen-sensitive and androgen-insensitive prostate cancer specimens.


RESULTS
cPLA2-alpha is present in all prostate cancer cells lines, but increased in androgen-insensitive cells. Inhibition with small interfering RNA or Wyeth-1 results in significant reductions in prostate cancer cell numbers, as a result of reduced proliferation as well as increased apoptosis, and this was also associated with a reduction in cPLA2-alpha activity. Expression of cyclin D1 and phosphorylation of Akt were also observed to decrease. Wyeth-1 inhibited PC3 xenograft growth by approximately 33% and again, also reduced cyclin D1. Immunohistochemistry of human prostate tissue revealed that phosphorylated cPLA2-alpha is increased when hormone refractory is reached.


CONCLUSIONS
Expression and activation of cPLA2-alpha are increased in the androgen-insensitive cancer cell line and tissue. Inhibition of cPLA2-alpha results in cells and xenograft tumor growth inhibition and serves as a potentially effective therapy for hormone refractory prostate cancer.
Patel
Manish I
MI
Department of Surgery, The University of Sydney, Sydney, Australia.
Singh
Jaskirat
J
Niknami
Marzieh
M
Kurek
Caroline
C
Yao
Mu
M
Lu
Sasa
S
Maclean
Fiona
F
King
Nicholas J C
NJ
Gelb
Michael H
MH
Scott
Kieran F
KF
Russell
Pamela J
PJ
Boulas
John
J
Dong
Qihan
Q
D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000032:analysis; D003600:Cytosol / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
C530104:CCND1 protein, human; D004791:Enzyme Inhibitors; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; D054513:Group IV Phospholipases A2