Intracellular unesterified arachidonic acid signals apoptosis

Abstract

Cyclooxygenase-2 (COX-2) is up-regulated in many cancers and is a rate-limiting step in colon carcinogenesis. Nonsteroidal antiinflammatory drugs, which inhibit COX-2, prevent colon cancer and cause apoptosis. The mechanism for this response is not clear, but it might result from an accumulation of the substrate, arachidonic acid, an absence of a prostaglandin product, or diversion of the substrate into another pathway. We found that colon adenocarcinomas overexpress another arachidonic acid-utilizing enzyme, fatty acid-CoA ligase (FACL) 4, in addition to COX-2. Exogenous arachidonic acid caused apoptosis in colon cancer and other cell lines, as did triacsin C, a FACL inhibitor. In addition, indomethacin and sulindac significantly enhanced the apoptosis-inducing effect of triacsin C. These findings suggested that unesterified arachidonic acid in cells is a signal for induction of apoptosis. To test this hypothesis, we engineered cells with inducible overexpression of COX-2 and FACL4 as ''sinks'' for unesterified arachidonic acid. Activation of the enzymatic sinks blocked apoptosis, and the reduction of cell death was inversely correlated with the cellular level of arachidonic acid. Inhibition of the COX-2 component by nonsteroidal antiinflammatory drugs restored the apoptotic response. Cell death caused by exposure to tumor necrosis factor ␣ or to calcium ionophore also was prevented by removal of unesterified arachidonic acid. We conclude that the cellular level of unesterified arachidonic acid is a general mechanism by which apoptosis is regulated and that COX-2 and FACL4 promote carcinogenesis by lowering this level.

Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions

“…Among them, ACS members are candidate molecules to induce cancer-selective cell death (Cao et al, 2000;. Our present data indicate the critical function of ACSL5 in glioma cell survival and suggest that this enzyme could be a rational therapeutic target.…”

“…This reaction is a critical step in several lipid metabolic pathways, including phospholipid biosynthesis, lipid modification of cellular proteins and b-oxidation (Coleman et al, 2002). ACSs are overexpressed in a variety of cancers (Cao et al, 2000(Cao et al, , 2001Yamashita et al, 2000;Sung et al, 2003Sung et al, , 2007Gassler et al, 2005;Liang et al, 2005;Yeh et al, 2006). Moreover, our recent screening identified an ACS inhibitor as a tumorselective inducer of apoptosis Mashima and Tsuruo, 2005).…”

Cyclo-oxygenase inhibition reduces tumour growth and metastasis in an orthotopic model of breast cancer

“…Selective COX-2 inhibition has been shown to induce apoptosis through a cytochrome C-dependent pathway in oesophageal cancer cells (Li et al, 2001). Arachidonic acid, the substrate for COX, stimulates apoptosis, thus enhanced COX-2 expression could inhibit apoptosis by decreasing arachidonic acid (Cao et al, 2000). We found that in vivo, COX inhibition increased apoptosis with no change in proliferation in the primary tumours relative to control.…”

Dietary PUFA and cancer

“…Only the SGF diet was associated with a reduction in the development of the nodules which could be related to the interaction between C 20 : 5n-3 and C 20 : 3n-6 (dihomo-GLA) which appear to synergistically control the metabolism of C 20 : 4n-6 and also serve as substrates for less potent prostanoid metabolites, such as PGE 3 and E 1 respectively. This control over C 20 : 4n-6 metabolism by the C 20 : 5n-3/C 18 : 3n-6 (GLA) dietary combination has important implications for the regulation of transcription factors and genes involved in signalling pathways affecting cell proliferation and apoptosis which can influence the development of hepatocyte nodules (41,43) .…”