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

Abstract

Purpose: Cytosolic phospholipase A2-a (cPLA 2 -a) provides intracellular arachidonic acid to supply both cyclooxygenase and lipoxygenase pathways. We aim to determine the expression and activation of cPLA 2 -a in prostate cancer cell lines and tissue and the effect of targeting cPLA 2 -a in vitro and in vivo. Experimental Design: The expression of cPLA 2 -a was determined in prostate cancer cells by reverse transcription-PCR,Western blot, and immunocytochemistry. Growth inhibition, apoptosis, and cPLA 2 -a activity were determined after inhibition with cPLA 2 -a small interfering RNA or inhibitor (Wyeth-1). Cytosolic PLA 2 -a inhibitor or vehicle was also administered to prostate cancer xenograft mouse models. Finally, the expression of phosphorylated cPLA 2 -a was determined by immunohistochemistry in human normal, androgen-sensitive and androgen-insensitive prostate cancer specimens. Results: cPLA 2 -a is present in all prostate cancer cells lines, but increased in androgen-insensitive cells. Inhibition with small interfering RNA or Wyeth-1results 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 -a activity. Expression of cyclin D1and phosphorylation of Akt were also observed to decrease. Wyeth-1inhibited PC3 xenograft growth by f33% and again, also reduced cyclin D1. Immunohistochemistry of human prostate tissue revealed that phosphorylated cPLA 2 -a is increased when hormone refractory is reached. Conclusions: Expression and activation of cPLA 2 -a are increased in the androgen-insensitive cancer cell line and tissue. Inhibition of cPLA 2 -a results in cells and xenograft tumor growth inhibition and serves as a potentially effective therapy for hormone refractory prostate cancer.Previous studies have shown that the eicosanoid pathway is activated in many types of cancers (1) including prostate (2 -9). Eicosanoids, which are the products of the cyclooxygenase (COX) and lipoxygenase pathways, contribute to cancer progression by promoting cell proliferation, motility, invasion, and angiogenesis (8 -10). Eicosanoids are synthesized from intracellular arachidonic acid, which is released from membrane phospholipids by the action of phospholipase A 2 (PLA 2 ; refs. 11,12). Of the known mammalian PLA 2 enzymes, cytosolic PLA 2 -a (cPLA 2 -a), an 85-kDa protein, is the predominant source of intracellular arachidonic acid for eicosanoid production.We have previously shown that expression of Annexin II, a calcium-dependent phospholipid-binding protein and inhibitory regulator of cPLA 2 -a, is lost in human prostate cancer (13). We have also reported that secretory PLA 2 -IIA (sPLA 2 -IIA), one of the secretory PLA 2 s, is overexpressed in prostate cancer cells including those remaining after androgen ablation therapy (14). The growth-promoting effect of sPLA 2 -IIA seems to be via cPLA 2 -a (14). These data have prompted us to investigate the role of cPLA 2 -a in prostate canc...

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“…Mechanistically, the function was explained by competition for the lipid substrates [96][97][98]. However, cPLA2 might be inhibited in a more direct manner [99].…”