- 期刊
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 Mitogenactivated Protein Kinases as Potential Targets
並列摘要
We previously reported that a novel alkylphospholipid type antitumor agent edelfosine (ET-18-O-CH3 ; 1-Ooctadecyl- 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-Δ12,14-prostaglandins J2 (15d-PGJ2). ET-18-O-CH3 treatment also enhanced the production of prostaglandin E2 (PGE2), 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 ERK1/2, 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-κB 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-κB signaling via COX-2 induction in MCF10A-ras cells, thereby inducing apoptosis of these cells.
延伸閱讀
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