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Eicosapentaenoic acid-induced apoptosis depends on acyl CoA-synthetase
Hilde Heimli1, Kristin Hollung, Christian A Drevon
1Institute for Nutrition Research, University of Oslo, Blindern, Oslo, Norway.
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.
Insights
Acyl-CoA synthetase (ACS) is crucial for EPA-induced apoptosis in lymphoma cells. Inhibiting ACS significantly reduces EPA
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Marine omega-3 fatty acids, like EPA, show anti-cancer properties by inhibiting proliferation and inducing cell death.
- EPA effectively induces apoptosis in Ramos lymphoma cells but not in U-698 cells.
- Acyl-CoA synthetase (ACS) expression is higher in EPA-sensitive Ramos cells than in EPA-insensitive U-698 cells.
Purpose of the Study:
- To investigate the role of ACS in EPA-induced apoptosis.
- To explore the potential of ACS in mediating the anti-cancer effects of marine omega-3 fatty acids.
Main Methods:
- Incubation of Ramos cells with triacsin C, an ACS inhibitor.
- Attempted overexpression of ACS4 in EPA-insensitive lymphoma cell lines and COS-1 cells.
- Measurement of cell-associated EPA, EPA activation, and triacylglycerol (TAG) levels.
Main Results:
- Triacsin C treatment reduced cell-associated EPA by 70% and EPA-induced apoptosis by 90% in Ramos cells.
- Overexpression of ACS4 in COS-1 cells increased EPA activation by fivefold and cell-associated EPA by 67%.
- COS-1 cells overexpressing ACS4 showed a 28% increase in cellular TAG levels upon EPA incubation.
Conclusions:
- ACS is an important enzyme in EPA-induced apoptosis in Ramos lymphoma cells.
- The findings suggest a mechanism for how dietary marine omega-3 polyunsaturated fatty acids may affect malignant cell growth.