Department of Materials and Life Science, Faculty of Science and Technology, Seikei University, Tokyo 180‑8633, Japan.
Department of Biochemical Engineering, Graduate School of Science and Engineering, Yamagata University, Yonezawa, Yamagata 992‑8510, Japan.
Mol Med Rep. 2019 Apr;19(4):2767-2773. doi: 10.3892/mmr.2019.9940. Epub 2019 Feb 5.
Polyunsaturated fatty acids are oxidized by non‑enzymatic or enzymatic reactions. The oxidized products are multifunctional. In this study, we investigated how oxidized fatty acids inhibit cell proliferation in cultured cells. We used polyunsaturated and saturated fatty acids, docosahexaenoic acid (DHA; 22:6), eicosapentaenoic acid (EPA; 20:5), linoleic acid (LA; 18:2), and palmitic acid (16:0). Oxidized fatty acids were produced by autoxidation of fatty acids for 2 days in the presence of a gas mixture (20% O2 and 80% N2). We found that oxidized polyunsaturated fatty acids (OxDHA, OxEPA and OxLA) inhibited cell proliferation much more effectively compared with un‑oxidized fatty acids (DHA, EPA and LA, respectively) in THP‑1 (a human monocytic leukemia cell line) and DLD‑1 (a human colorectal cancer cell line) cells. In particular, OxDHA markedly inhibited cell proliferation. DHA has the largest number of double bonds and is most susceptible to oxidation among the fatty acids. OxDHA has the largest number of highly active oxidized products. Therefore, the oxidative levels of fatty acids are associated with the anti‑proliferative activity. Moreover, caspase‑3/7 was activated in the cells treated with OxDHA, but not in those treated with DHA. A pan‑caspase inhibitor (zVAD‑fmk) reduced the cell death induced by OxDHA. These results indicated that oxidized products from polyunsaturated fatty acids induced apoptosis in cultured cells. Collectively, the switch between cell survival and cell death may be regulated by the activity and/or number of oxidized products from polyunsaturated fatty acids.
多不饱和脂肪酸可通过非酶或酶促反应氧化。氧化产物具有多功能性。在这项研究中，我们研究了氧化脂肪酸如何抑制培养细胞中的细胞增殖。我们使用多不饱和和饱和脂肪酸，二十二碳六烯酸（DHA；22:6），二十碳五烯酸（EPA；20:5），亚油酸（LA；18:2）和棕榈酸（16:0）。通过脂肪酸在存在气体混合物（20%O2 和 80%N2）的情况下自动氧化 2 天来产生氧化脂肪酸。我们发现，与未氧化的脂肪酸（DHA、EPA 和 LA）相比，氧化的多不饱和脂肪酸（OxDHA、OxEPA 和 OxLA）在 THP-1（人单核白血病细胞系）和 DLD-1（人结直肠癌细胞系）细胞中更有效地抑制细胞增殖。特别是 OxDHA 明显抑制细胞增殖。DHA 在脂肪酸中具有最多的双键，并且最易氧化。OxDHA 具有最多的高活性氧化产物。因此，脂肪酸的氧化水平与抗增殖活性有关。此外，在用 OxDHA 处理的细胞中激活了半胱天冬酶-3/7，但在用 DHA 处理的细胞中未激活。泛半胱天冬酶抑制剂（zVAD-fmk）降低了 OxDHA 诱导的细胞死亡。这些结果表明，多不饱和脂肪酸的氧化产物在培养细胞中诱导细胞凋亡。总的来说，细胞存活和细胞死亡之间的转换可能受到多不饱和脂肪酸氧化产物的活性和/或数量的调节。
