2006 Fiscal Year Final Research Report Summary
Marignancy of cell-proliferative diseases by unusual production of phospholipid mediators in response to oxidative stress
| Project/Area Number |
16390034
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Environmental pharmacy
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| Research Institution | The University of Tokushima |
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Principal Investigator |
TOKUMURA Akira The University of Tokushima, Graduate School, Institute of Health Sciences, Associate professor, 大学院ヘルスバイオサイエンス研究部, 助教授 (00035560)
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| Co-Investigator(Kenkyū-buntansha) |
FUKUZAWA Kenji The University of Tokushima, Graduate School, Institute of Health Sciences, Professor, 大学院ヘルスバイオサイエンス研究部, 教授 (90035551)
YAMANO Shuji The University of Tokushima, School of Medicine, Professor, 医学部, 教授 (30166772)
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| Project Period (FY) |
2004 – 2006
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| Keywords | oxidative stress / lysophospholipid / lysophospholipase D / lysophosphatidic acid / platelet activating factor / oxidized phospholipid / atherosclerosis / cancer metastasis |
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| Research Abstract |
First, we devised useful quantitative methods for primary (hydroperoxides) and secondary [platelet-activating factor (PAF)-like lipid] products of peroxidized phosphatidylcholines (PC). Using these methods, we found that three PAF-like lipids having a short chain acyl group were generated during incubation of human plasma with Cu^+ [dicarboxylate(DC)-containing PC > dicarboxylate semialdehyde(DCsa)-containing PC > monocarboxylate(MC)-containing PC]. The predominant PAF-like lipid in human plasma incubated with Fe^<2+> was MC-PC. A minor amount of DCsa-PC, but not DC-PC, was also detected. Both DC-PC and DCsa-PC stimulated the proliferation of human umbilical vein endothelial cells at concentrations less than 25 μM, but induced the apoptosis of the endothelial cells at higher concentrations.
We found that lysophospholipase D (lysoPLD) partially purified from human plasma and recombinant lysoPLD/autotaxin hydrolyzed PAF-like lipids and their deacylated product (lysophosphatidylcholine) in
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to phosphatidic acid having a short chain acyl group and lysophosphatidic acid that possess a potent cell-proliferative effect on various animal cells.
We devised a convenient assay for lysoPLD activity on a microplate reader. With use of the assay, we found that lysoPLD activities in sera from patients suffering from preeclamptia and preterm labor were higher than that observed for women under normal pregnancy, We also found that lysoPLD activities in peritoneal fluids from patients with ovarian cancer, cystadenoma, dermoid cyst and myoma uteri were higher than those for patients with other gynecological disease.
From these results, we suggested that increased oxidative stress in animal body caused peroxidation of PC in biomembranes and lipoproteins followed by the cleavage of C-C bond(s), generating PAF-like lipid. The PAF-like lipids and their deacylated product were then hydrolyzed by lysoPLD activity in various biological fluids into bioactive phosphatidic acid and lysophosphatidic acid. Our results indicate that high lysoPLD activity in the biological fluids from preeclamptic patients with injured vascular endothelium and patients with gynecological tumor might be a factor that could affect the malignancy of the diseases Less
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