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Cytosolic phospholipase A2-alpha: a potential therapeutic target for prostate cancer.

AbstractPURPOSE:
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.
EXPERIMENTAL DESIGN:
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.
AuthorsManish I Patel, Jaskirat Singh, Marzieh Niknami, Caroline Kurek, Mu Yao, Sasa Lu, Fiona Maclean, Nicholas J C King, Michael H Gelb, Kieran F Scott, Pamela J Russell, John Boulas, Qihan Dong
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 24 Pg. 8070-9 (Dec 15 2008) ISSN: 1078-0432 [Print] United States
PMID19088022 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • CCND1 protein, human
  • Enzyme Inhibitors
  • Cyclin D1
  • Proto-Oncogene Proteins c-akt
  • Group IV Phospholipases A2
Topics
  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclin D1 (analysis)
  • Cytosol (enzymology)
  • Enzyme Inhibitors (therapeutic use)
  • Group IV Phospholipases A2 (antagonists & inhibitors)
  • Humans
  • Male
  • Phosphorylation
  • Prostatic Neoplasms (drug therapy, enzymology, pathology)
  • Proto-Oncogene Proteins c-akt (metabolism)

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