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 alpha 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.

• Authors: Y Cao, A T Pearman, G A Zimmerman, T M McIntyre, S M Prescott
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 97 Issue 21 Pg. 11280-5 (Oct 10 2000) ISSN: 0027-8424 [Print] United States
• PMID: 11005842 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antioxidants
• Isoenzymes
• Membrane Proteins
• Repressor Proteins
• Saccharomyces cerevisiae Proteins
• Tumor Necrosis Factor-alpha
• Arachidonic Acid
• Cyclooxygenase 2
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• CASP3 protein, human
• Caspase 3
• Caspases
• Coenzyme A Ligases
• FAA2 protein, S cerevisiae
• long-chain-fatty-acid-CoA ligase

Topics

• Adenocarcinoma (enzymology, pathology)
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Antioxidants (pharmacology)
• Apoptosis (drug effects, physiology)
• Arachidonic Acid (physiology)
• Caspase 3
• Caspases (metabolism)
• Cell Line
• Coenzyme A Ligases (metabolism)
• Colonic Neoplasms (enzymology, pathology)
• Cyclooxygenase 2
• Enzyme Activation
• Enzyme-Linked Immunosorbent Assay
• Esterification
• Humans
• Isoenzymes (metabolism)
• Membrane Proteins
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Repressor Proteins
• Reverse Transcriptase Polymerase Chain Reaction
• Saccharomyces cerevisiae Proteins
• Tumor Necrosis Factor-alpha (physiology)