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The antitumor ether lipid edelfosine (ET-18-O-CH3) induces apoptosis in H-ras transformed human breast epithelial cells: by blocking ERK1/2 and p38 mitogen-activated protein kinases as potential targets

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Authors
Na, Hye-Kyung; Surh, Young-Joon
Issue Date
2008-01
Citation
Asia Pacific Journal of Clinical Nutrition, Vol.17, pp.204-207
Keywords
ET-18-O-CH3edelfosineapoptosisCOX-2MCF10A-ras cells
Abstract
We previously reported that a novel alkylphospholipid type antitumor agent edelfosine (ET-18-O-CH3; 1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine) induced apoptosis in human breast epithelial cells transfected with the H-ras oncogene (MCF10A-ras) which was causally linked to cyclooxygenase-2 (COX-2) up-regulation and production of 15-deoxy-Delta(12,14)-prostaglandins J(2) (15d-PGJ2). ET-18-O-CH3 treatment also enhanced the production of prostaglandin E-2 (PGE(2)), a major COX-2 product. In this study, we found that ET-18-O-CH3 treatment resulted in elevated mRNA expression of the PGE2 receptor subunit, EP2 receptor. Exogenously added PGE2 inhibited the growth of MCF10A-ras cells and induced proteolytic cleavage of caspase 3. ET-18-O-CH3 also inhibited constitutive activation of ERK 1/2, p38 MAPK, and Akt/protein kinase B, which was blunted by a selective COX-2 inhibitor SC58635. In addition, ET-18-O-CH3 inhibited DNA binding activity of NF-kappa B in MCF10A-ras cells, and this was again attenuated by SC58635. Based on these findings, it is likely that ET-18-O-CH3 inactivates ERK1/2, Akt, and NF-kappa B signaling via COX-2 induction in MCF10A-ras cells, thereby inducing apoptosis of these cells.
ISSN
0964-7058
URI
https://hdl.handle.net/10371/172587
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Journal Papers (저널논문_분자의학 및 바이오제약학과)
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