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.
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 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-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-kappaB signaling via COX-2 induction in MCF10A-ras cells, thereby inducing apoptosis of these cells.
Na
Hye-Kyung
HK
National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
Surh
Young-Joon
YJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001940:Breast / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D002461:Cell Line, Transformed; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects; D011905:Genes, ras; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010742:Phospholipid Ethers / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
D000970:Antineoplastic Agents; D010742:Phospholipid Ethers; D012333:RNA, Messenger; C026659:edelfosine; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone