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

• Published in: Clinical cancer research 2008-12, Vol.14 (24), p.8070-8079
• Main Authors: Patel, Manish I, Singh, Jaskirat, Niknami, Marzieh, Kurek, Caroline, Yao, Mu, Lu, Sasa, Maclean, Fiona, King, Nicholas J C, Gelb, Michael H, Scott, Kieran F, Russell, Pamela J, Boulas, John, Dong, Qihan
• Format: Article
• Language: English
• Subjects: angiogenesis; Apoptosis; Cell Line, Tumor; Cell Proliferation; cPLA; Cyclin D1 - analysis; Cytosol - enzymology; eicosanoids; Enzyme Inhibitors - therapeutic use; Group IV Phospholipases A2 - antagonists & inhibitors; Humans; Male; Phosphorylation; prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-akt - metabolism
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-0566

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.