Cytosolic Phospholipase A2-α: A Potential Therapeutic Target for Prostate Cancer

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