Arachidonoyl ethanolamide (AEA)‐induced apoptosis is mediated by J‐series prostaglandins and is enhanced by fatty acid amide hydrolase (FAAH) blockade

Abstract

The endocannabinoid arachidonoyl ethanolamide (AEA) is a potent inducer of tumor cell apoptosis however its mechanism of cytotoxicity is unclear. A previous report from our laboratory showed that AEA induced cell death in a COX-2-dependent manner and in this report our data indicate that AEA-induced apoptosis is mediated by COX-2 metabolic products of the J-series. In experiments conducted with JWF2 keratinocytes which overexpress COX-2, AEA caused a concentration-regulated increase in J-series prostaglandin production and apoptosis. Similarly, cell treatment with exogenously added J-series prostaglandins (15-deoxy, Δ 12,14 PGJ 2 and PGJ 2 ) induced apoptosis. AEA-induced apoptosis was inhibited by the antioxidant, N-acetyl cysteine, indicating that reactive oxygen species generation was required for apoptosis. Using antagonists of cannabinoid receptor 1, cannabinoid receptor 2, or TRPV1, it was observed that cannabinoid receptor inhibition did not block AEA-mediated cell death. In contrast, an inhibitor of fatty acid amide hydrolase (FAAH) potentiated AEA-induced J-series PG synthesis and apoptosis. These results suggest that the metabolism of AEA to J-series PGs regulates the induction of apoptosis in cells with elevated COX-2 levels. Our data further indicate that the proapoptotic activity of AEA can be enhanced by combining it with an inhibitor of FAAH. As such, AEA may be an effective agent to eliminate tumor cells that overexpress COX-2.

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).…”

Enhanced microglial activity in FAAH−/− animals

“…Cyclooxygenase 2 is involved in the degradation of AEA in the brain [43] and this pathway may be prominent in FAAH -/-mice. The enhanced level of prostamides [43] in the mouse brain and possibly prostaglandins (measured in keratinocytes) [44] due to this alternative degradation pathway and the induction of arachidonic acid pathway due to the enhanced AEA levels [45] together can lead to an elevated chronic pro-inflammatory signaling in FAAH -/-animals.…”

Receptor-dependent and receptor-independent endocannabinoid signaling: A therapeutic target for regulation of cancer growth

“…Recently we showed that AEA-induced cytotoxicity was mediated by the production of proapoptotic, J-series prostaglandins in tumorigenic keratinocytes that overexpress COX-2 (Van Dross, 2009;Kuc et al, 2012). In addition, resistance to AEA-induced cytotoxicity was observed in non-tumorigenic keratinocytes with low basal COX-2 expression however, these cells underwent cell death when transfected with an expression plasmid containing COX-2.…”