ET-18-O-CH3-induced apoptosis is causally linked to COX-2 upregulation in H-ras transformed human breast epithelial cells.
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.
Na
Hye-Kyung
HK
National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
Inoue
Hiroyasu
H
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*; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D011905:Genes, ras; D006801:Humans; D047495:PPAR gamma / Q000378:metabolism; D010742:Phospholipid Ethers / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation
C477819:15-deoxyprostaglandin J2; D000970:Antineoplastic Agents; D047495:PPAR gamma; D010742:Phospholipid Ethers; C026659:edelfosine; D051546:Cyclooxygenase 2; D015230:Prostaglandin D2