Cytochrome P450 2J2 promotes the neoplastic phenotype of carcinoma cells and is up-regulated in human tumors.
Cytochrome P450 (CYP) arachidonic acid epoxygenase 2J2 converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids, which exert diverse biological activities in cardiovascular system and endothelial cells. However, it is unknown whether this enzyme highly expresses and plays any role in cancer. In this study, we found that very strong and selective CYP2J2 expression was detected in human carcinoma tissues in 101 of 130 patients (77%) as well as eight human carcinoma cell lines but undetectable in adjacent normal tissues and nontumoric human cell lines by Western, reverse transcription-PCR, and immunohistochemical staining. In addition, forced overexpression of CYP2J2, and CYP BM3F87V or addition of epoxyeicosatrienoic acids (EET) in cultured carcinoma cell lines in vitro markedly accelerated proliferation by analyses of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, cell accounts, and cell cycle analysis, and protected carcinoma cells from apoptosis induced by tumor necrosis factor alpha (TNF-alpha) in cultures. In contrast, antisense 2J2 transfection or addition of epoxygenase inhibitors 17-ODYA inhibited proliferation and accelerated cell apoptosis induced by TNF-alpha. Examination of signaling pathways on the effects of CYP2J2 and EETs revealed activation of mitogen-activated protein kinases and PI3 kinase-AKT systems and elevation of epithelial growth factor receptor phosphorylation level. These results strongly suggest that CYP epoxygenase 2J2 plays a previously unknown role in promotion of the neoplastic cellular phenotype and in the pathogenesis of a variety of human cancers.
Jiang
Jian-Gang
JG
Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, PR China.
Chen
Chun-Lian
CL
Card
Jeffrey W
JW
Yang
Shilin
S
Chen
Ji-Xiong
JX
Fu
Xiang-Ning
XN
Ning
Yao-Gui
YG
Xiao
Xiao
X
Zeldin
Darryl C
DC
Wang
Dao Wen
DW
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D002277:Carcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D010105:Oxygenases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
D015126:8,11,14-Eicosatrienoic Acid; D014408:Biomarkers, Tumor; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System; D066246:ErbB Receptors; D010105:Oxygenases; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; C000717350:CYP2J2 protein, human; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid