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ET‐18‐O‐CH 3 ‐induced apoptosis is causally linked to COX‐2 upregulation in H‐ras transformed human breast epithelial cells
Author(s) -
Na Hye-Kyung,
Inoue Hiroyasu,
Surh Young-Joon
Publication year - 2005
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2005.09.094
Subject(s) - apoptosis , downregulation and upregulation , cancer research , chemistry , peroxisome proliferator activated receptor , jurkat cells , cell culture , receptor , microbiology and biotechnology , biology , gene , biochemistry , immunology , t cell , genetics , immune system
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‐CH 3 (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‐CH 3 ‐induced apoptosis, suggesting that COX‐2 induction by this drug is causally linked to its apoptosis inducing activity. ET‐18‐O‐CH 3 enhanced the transcriptional activities of cyclic AMP response element which is a key regulator of COX‐2 expression. 15‐Deoxy‐Δ 12,14 prostaglandin J 2 is, an endogenous ligand for peroxisome proliferator‐activated receptor γ (PPARγ), has been known to possess proapoptotic potential in diverse cell types. ET‐18‐O‐CH 3 treatment resulted in elevated release of 15d‐PGJ 2 and DNA binding and transcriptional activity of PPARγ. Based on these findings, it is likely that ET‐18‐O‐CH 3 induces COX‐2 expression and production of 15d‐PGJ 2 which may mediate the ET‐18‐O‐CH 3 ‐induced apoptosis in MCF10A‐ ras cells.