Binding of nonsteroidal antiinflammatory drugs to the alpha-subunit of the trifunctional protein of long chain fatty acid oxidation.
Nonsteroidal antiinflammatory drugs (NSAIDs) reduce the growth of colorectal carcinoma cell lines in vitro. The mechanism appears to be independent of cyclooxygenases, and the long chain fatty acid pathway has been suggested as an alternative inhibitory target. We now report that all NSAIDs tested bound to the alpha-subunit of the trifunctional protein of the long chain fatty acid oxidation pathway, as assessed by competition with 125I-[Nle15]-gastrin2,17 in a covalent cross-linking assay. Furthermore the NSAIDs diclofenac and ibuprofen inhibited the 3-hydroxyacyl-CoA dehydrogenase activity intrinsic to the alpha-subunit. The potencies of NSAIDs as inhibitors of human colon carcinoma cell proliferation correlated well with their affinities for the alpha-subunit. We conclude that inhibition of long chain fatty acid oxidation via binding of NSAIDs to the alpha-subunit of the trifunctional protein may contribute to the inhibitory effects of NSAIDs on colorectal carcinoma cell growth.
Baldwin
G S
GS
Department of Surgery, Austin Campus, Austin & Repatriation Medical Centre, Melbourne Tumour Biology Branch, Melbourne, Victoria, Australia.
Murphy
V J
VJ
Yang
Z
Z
Hashimoto
T
T
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D002455:Cell Division; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000378:metabolism; D003432:Cross-Linking Reagents; D005755:Gastrins / Q000378:metabolism; D006801:Humans; D063991:Mitochondrial Trifunctional Protein; D009097:Multienzyme Complexes / Q000378:metabolism*; D010084:Oxidation-Reduction; D011485:Protein Binding; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003432:Cross-Linking Reagents; D005755:Gastrins; D009097:Multienzyme Complexes; D015094:3-Hydroxyacyl CoA Dehydrogenases; D063991:Mitochondrial Trifunctional Protein