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.
Surrel
Fanny
F
Institut de Pharmacologie Moléculaire et Cellulaire, Université de Nice Sophia Antipolis et Centre National de la Recherche Scientifique, 06560 Valbonne, France.
Jemel
Ikram
I
Boilard
Eric
E
Bollinger
James G
JG
Payré
Christine
C
Mounier
Carine M
CM
Talvinen
Kati A
KA
Laine
Veli J O
VJ
Nevalainen
Timo J
TJ
Gelb
Michael H
MH
Lambeau
Gérard
G
D000818:Animals; D001483:Base Sequence; D055162:Biocatalysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D017403:In Situ Hybridization; D008055:Lipids / Q000096:biosynthesis*; D051379:Mice; D054467:Phospholipases A2 / Q000494:pharmacology*; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D008055:Lipids; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D054467:Phospholipases A2