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

Abstract

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-Ooctadecyl-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-D 12,14 prostaglandin J 2 is, an endogenous ligand for peroxisome proliferator-activated receptor c (PPARc), 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 PPARc. 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.

COX-2 and PPAR-γ Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells

“…Third, our results support several other investigations pointing to a pivotal role of PPAR-g activated by COX-2-dependent PGs of the D-and J-series in the proapoptotic action of several substances including well-established chemotherapeutics (19,(21)(22)(23)(24), thereby challenging the traditional view considering COX-2 inhibition as an anticancer strategy. In line with these data, overexpression of COX-2 decreased proliferation and increased apoptosis of osteosarcoma cells (43) and protected rather than sensitized animals to experimental skin tumor development (44).…”

“…Although cannabidiol shares the PG-dependent activation of PPAR-g with several other substances (19,(21)(22)(23)(24), there are also data showing a direct binding of cannabidiol to PPAR-g independent of endogenous PGs followed by an increase of its transcriptional activity (35). In our hands, NS-398 or GW9662 alone profoundly but in most instances not completely reversed the cytotoxic and proapoptotic action of cannabidiol, whereas a combined treatment of cannabidiol-exposed cells with NS-398 and GW9662 fully restored control conditions.…”

“…In fact, recent studies indicate a COX-2-dependent pathway underlying apoptosis elicited by the cannabinoid compounds anandamide and its analog R(þ)-methanandamide (18,19). In addition, COX-2 upregulation has been reported to be involved in the proapoptotic action of stearoylethanolamide (20), the alkylphospholipids edelfosin and perifosin (21,22), as well as the chemotherapeutics cisplatin, 5-fluorouracil, and paclitaxel (23,24). About the mechanism underlying COX-2-dependent apoptosis, several studies provided evidence for an activation of the transcription factor PPAR-g by COX-2-dependent PGs of the D-and Jseries (19,(24)(25)(26).…”

Induction but not inhibition of COX-2 confers human lung cancer cell apoptosis by celecoxib

“…In addition and in contrast to the traditional view implying a protumorigenic function of COX-2 ( 19,20 ), overexpression of COX-2 decreased proliferation and increased apoptosis of osteosarcoma cells ( 21 ), and it protected rather than sensitized animals to experimental skin tumor development ( 22 ). In line with these fi ndings, COX-2 upregulation has emerged as a proapoptotic mechanism shared by various antitumorigenic compounds (23)(24)(25)(26)(27)(28)(29)(30).…”

Decisive role of cyclooxygenase-2 and lipocalin-type prostaglandin D synthase in chemotherapeutics-induced apoptosis of human cervical carcinoma cells

“…Moreover, R( þ )-methanandamide, a stable analogue of the endocannabinoid anandamide, was recently shown to induce apoptosis of neuroglioma cells via a COX-2-dependent mechanism (Hinz et al, 2004;Eichele et al, 2006). Further evidence supporting the involvement of COX-2-derived PGs in proapoptotic and cytotoxic effects of diverse other substances was provided by studies performed on human leukemia (Chen et al, 2005), C6 rat glioma (Maccarrone et al, 2002), colorectal carcinoma (Dommels et al, 2003) and H-ras-transformed breast epithelial cells (Na et al, 2005).…”