Cytosolic phospholipase A ₂-α: a potential therapeutic target for prostate cancer

Purpose: Cytosolic phospholipase A2-α (cPLA ₂-α) provides intracellular arachidonic acid to supply both cyclooxygenase and lipoxygenase pathways. We aim to determine the expression and activation of cPLA ₂-α in prostate cancer cell lines and tissue and the effect of targeting cPLA ₂-α in vitro and in vivo. Experimental Design: The expression of cPLA ₂-α was determined in prostate cancer cells by reverse transcription-PCR,Western blot, and immunocytochemistry. Growth inhibition, apoptosis, and cPLA ₂-α activity were determined after inhibition with cPLA ₂-α small interfering RNA or inhibitor (Wyeth-1). Cytosolic PLA ₂-α inhibitor or vehicle was also administered to prostate cancer xenograft mouse models. Finally, the expression of phosphorylated cPLA ₂-α was determined by immunohistochemistry in human normal, androgen-sensitive and androgen-insensitive prostate cancer specimens. Results: cPLA ₂-α 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 cPLA ₂-α activity. Expression of cyclin D1 and phosphorylation of Akt were also observed to decrease. Wyeth-1 inhibited PC3 xenograft growth by ∼33% and again, also reduced cyclin D1. Immunohistochemistry of human prostate tissue revealed that phosphorylated cPLA ₂-α is increased when hormone refractory is reached. Conclusions: Expression and activation of cPLA ₂-α are increased in the androgen-insensitive cancer cell line and tissue. Inhibition of cPLA ₂-α results in cells and xenograft tumor growth inhibition and serves as a potentially effective therapy for hormone refractory prostate cancer.