title: Cytosolic phospholipase A2-alpha: a potential therapeutic target for prostate cancer.
abstract: 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.
authors.affiliation: Department of Surgery, The University of Sydney, Sydney, Australia.
authors.forename: Manish I
authors.initials: MI
authors.lastname: Patel
authors.forename: Jaskirat
authors.initials: J
authors.lastname: Singh
authors.forename: Marzieh
authors.initials: M
authors.lastname: Niknami
authors.forename: Caroline
authors.initials: C
authors.lastname: Kurek
authors.forename: Mu
authors.initials: M
authors.lastname: Yao
authors.forename: Sasa
authors.initials: S
authors.lastname: Lu
authors.forename: Fiona
authors.initials: F
authors.lastname: Maclean
authors.forename: Nicholas J C
authors.initials: NJ
authors.lastname: King
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.forename: Kieran F
authors.initials: KF
authors.lastname: Scott
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Russell
authors.forename: John
authors.initials: J
authors.lastname: Boulas
authors.forename: Qihan
authors.initials: Q
authors.lastname: Dong
mesh_terms: 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
chemical_list: C530104:CCND1 protein, human; D004791:Enzyme Inhibitors; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; D054513:Group IV Phospholipases A2