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FEBS Lett. 2005 Nov 7;579(27):6279-87. Epub 2005 Oct 14.

ET-18-O-CH3-induced apoptosis is causally linked to COX-2 upregulation in H-ras transformed human breast epithelial cells.

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National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.


Abnormally elevated expression of cyclooxygenase-2 (COX-2) has been frequently observed in transformed or malignant cells, and certain non-steroidal anti-inflammatory drugs with COX-2 inhibitory activity exert anti-neoplastic or chemopreventive effects. Contrary to this notion, we have found that a novel alkylphospholipid type antitumor agent ET-18-O-CH3 (1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine) induces COX-2 expression in H-ras transformed human breast epithelial cells (MCF10A-ras) while it causes apoptosis at the same concentration range. The addition of a selective COX-2 inhibitor SC-58635 and COX-2 gene knock down with the siRNA blocked ET-18-O-CH3-induced apoptosis, suggesting that COX-2 induction by this drug is causally linked to its apoptosis inducing activity. ET-18-O-CH3 enhanced the transcriptional activities of cyclic AMP response element which is a key regulator of COX-2 expression. 15-Deoxy-Delta(12,14) prostaglandin J2 is, an endogenous ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), has been known to possess proapoptotic potential in diverse cell types. ET-18-O-CH3 treatment resulted in elevated release of 15d-PGJ2 and DNA binding and transcriptional activity of PPARgamma. Based on these findings, it is likely that ET-18-O-CH3 induces COX-2 expression and production of 15d-PGJ2 which may mediate the ET-18-O-CH3-induced apoptosis in MCF10A-ras cells.

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