Phospholipase A2 activity of peroxiredoxin 6 promotes invasion and metastasis of lung cancer cells.
Peroxiredoxins (PRDX) are a family of thiol-dependent peroxidases. Among the six mammalian members of this family, PRDX6 is the only protein that additionally exhibits phospholipase A(2) (PLA(2)) activity. The physiologic role of this interesting PRDX6 feature is largely unknown at present. In this study, we show that PRDX6 increases the metastatic potential of lung cancer cells. Functional analyses of the enzymatic activities of PRDX6, using specific pharmacologic inhibitors and mutagenesis studies, reveal that both peroxidase and PLA(2) activities are required for metastasis. Specifically, peroxidase activity facilitates the growth of cancer cells, and PLA(2) activity promotes invasiveness. Further investigation of the latter event discloses that PLA(2) activity promotes accumulation of arachidonic acid, which, in turn, induces the invasive pathway involving p38 kinase, phosphoinositide 3-kinase, Akt, and urokinase-type plasminogen activator. This study is the first to define the functions of the enzymatic activities of PRDX6 in metastasis and to show the involvement of arachidonic acid in PRDX6 action in intact cells. These novel findings provide a significant step toward elucidating the role of PRDX6 in cancer and the mechanism of its action. Mol Cancer Ther; 9(4); 825-32. (c)2010 AACR.
Ho
Jin-Nyoung
JN
Laboratory of Radiation Tumor Physiology, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706, Korea.
Lee
Seung Bum
SB
Lee
Seung-Sook
SS
Yoon
Sung Hwan
SH
Kang
Ga Young
GY
Hwang
Sang-Gu
SG
Um
Hong-Duck
HD
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001835:Body Weight; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009929:Organ Size; D054465:Peroxiredoxin VI / Q000378:metabolism*; D054467:Phospholipases A2 / Q000378:metabolism*; D014162:Transfection
D016718:Arachidonic Acid; C515977:PRDX6 protein, human; D054465:Peroxiredoxin VI; D054467:Phospholipases A2