Group X phospholipase A2 stimulates the proliferation of colon cancer cells by producing various lipid mediators.

Among mammalian secreted phospholipases A2 (sPLA(2)s), the group X enzyme has the most potent hydrolyzing capacity toward phosphatidylcholine, the major phospholipid of cell membrane and lipoproteins. This enzyme has recently been implicated in chronic inflammatory diseases such as atherosclerosis and asthma and may also play a role in colon tumorigenesis. We show here that group X sPLA(2) [mouse (m)GX] is one of the most highly expressed PLA(2) in the mouse colon and that recombinant mouse and human enzymes stimulate proliferation and mitogen-activated protein kinase activation of various colon cell lines, including Colon-26 cancer cells. Among various recombinant sPLA(2)s, mGX is the most potent enzyme to stimulate cell proliferation. Based on the use of sPLA(2) inhibitors, catalytic site mutants, and small interfering RNA silencing of cytosolic PLA(2)alpha and M-type sPLA(2) receptor, we demonstrate that mGX promotes cell proliferation independently of the receptor and via its intrinsic catalytic activity and production of free arachidonic acid and lysophospholipids, which are mitogenic by themselves. mGX can also elicit the production of large amounts of prostaglandin E2 and other eicosanoids from Colon-26 cells, but these lipid mediators do not play a role in mGX-induced cell proliferation because inhibitors of cyclooxygenases and lipoxygenases do not prevent sPLA(2) mitogenic effects. Together, our results indicate that group X sPLA(2) may play an important role in colon tumorigenesis by promoting cancer cell proliferation and releasing various lipid mediators involved in other key events in cancer progression.

Cloning of a novel phospholipase A2 from the cnidarian Adamsia carciniopados.

PLA2 catalytic activity was detected in homogenised tissues, including tentacles and acontia (structures for preying and defence, respectively), of the sea anemone Adamsia carciniopados. Nested reverse transcription polymerase chain reaction (RT PCR) with degenerate primers and rapid amplification of cDNA ends (RACE) were used to clone a novel phospholipase A2 from Adamsia carciniopados (AcPLA2). AcPLA2 contains a putative prepropeptide of 37 residues, ending with a basic doublet followed by a mature protein of 119 amino acids, including 12 cysteines. AcPLA2 displays only 30-42% similarity with other known secretory PLA2s (sPLA2). C-terminal extension, typical of groups II and X PLA2s, is absent. Predicted molecular weight and pI of the mature protein are 13.5 kDa and 9.1, respectively. Structural features and phylogenetic analysis set AcPLA2 apart from the known sPLA2s and define this molecule in the ancient metazoan phylum Cnidaria as a member of a new class of sPLA2s.