title: Eicosapentaenoic acid-induced apoptosis depends on acyl CoA-synthetase.
abstract: Marine n-3 FA are known to inhibit proliferation or induce cell death in several cancer cell lines. We have previously reported that EPA promotes apoptosis in the lymphoma cell line Ramos, whereas the U-698 cell line is insensitive to EPA. Furthermore, acyl-CoA synthetase (ACS) is expressed to a higher extent in Ramos cells compared to U-698 cells. To investigate the importance of ACS in EPA-induced apoptosis, we incubated Ramos cells with triacsin C, an inhibitor of ACS. This caused a 70% reduction in the amount of cell-associated EPA and diminished activation of EPA. In addition, triacsin C caused a 90% reduction in EPA-induced apoptosis. Several different approaches were tried to overexpress ACS4 in EPA-insensitive lymphoma cell lines, but we did not obtain viable cells with high expression of acyl-CoA activation. However, we show that overexpression of ACS4 in the more robust COS-1 cells caused up to a fivefold increase in activation of EPA and a 67% increase in the amount of cell-associated radiolabeled EPA. Furthermore, we observed 28% elevated cellular level of TAG in EPA-incubated COS-1 cells overexpressing ACS4. The present study provides new information about ACS as an important enzyme for EPA-induced apoptosis in Ramos cells. Our data offer a potential mechanism that may explain the effect of dietary marine n-3 PUFA on growth of certain malignant cells.
authors.affiliation: Institute for Nutrition Research, University of Oslo, Blindern, Oslo, Norway.
authors.forename: Hilde
authors.initials: H
authors.lastname: Heimli
authors.forename: Kristin
authors.initials: K
authors.lastname: Hollung
authors.forename: Christian A
authors.initials: CA
authors.lastname: Drevon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D019556:COS Cells; D002478:Cells, Cultured; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D015118:Eicosapentaenoic Acid / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D014226:Triazenes / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D014226:Triazenes; D014280:Triglycerides; C034613:triacsin C; D015118:Eicosapentaenoic Acid; D003066:Coenzyme A Ligases