Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, TX, USA.
Cancer Prev Res (Phila). 2011 Aug;4(8):1267-74. doi: 10.1158/1940-6207.CAPR-10-0368. Epub 2011 Apr 13.
An alteration of mitochondrial function can result in disruption of redox homeostasis and is associated with abnormal cancer cell growth. Manganese superoxide dismutase (SOD2) and glutathione peroxidase 4 (Gpx4) are two of the most important antioxidant defense enzymes that protect cells against oxidative stress. We had previously shown that n-3 polyunsaturated fatty acids (PUFA) promote colonocyte apoptosis, a marker of colon cancer risk, in part by enhancing phospholipid oxidation. To elucidate the mechanisms regulating oxidative stress-induced apoptosis in vivo, we fed heterozygous SOD2(Het), Gpx4(Het), and transgenic Gpx4(Tg) mice diets containing either 15% corn oil by weight (CO, enriched in n-6 PUFA) or 3.5% CO + 11.5% fish oil (FO, enriched in n-3 PUFA) for 4 weeks. Our data showed that (i) genetic predeposition to oxidative stress facilitates apoptosis in the mouse colon (Gpx4(Het) > SOD2(Het) > Wt > Gpx4(Tg)), (ii) dietary n-3 PUFA have an additive effect on the induction of apoptosis in Gpx4(Het) and SOD2(Het) mice; and (iii) dietary n-3 PUFA reverse the phenotype in oxidatively protected Gpx4(Tg) mice by elevating apoptosis to a level observed in wild-type (Wt; control) animals. Complimentary experiments examining colonic mitochondrial bioenergetic profiles indicate that FO-fed mice exhibit a significantly (P < 0.05) increased respiration-induced proton leak relative to control CO treatment. This finding was consistent with a loss of membrane potential in response to chronic oxidative stress and supports the contention that n-3 PUFA alter mitochondrial metabolic activity, thereby enhancing apoptosis and reducing colon cancer risk.
线粒体功能的改变可能导致氧化还原稳态的破坏，并与异常的癌细胞生长有关。锰超氧化物歧化酶（SOD2）和谷胱甘肽过氧化物酶 4（Gpx4）是两种最重要的抗氧化防御酶，可保护细胞免受氧化应激。我们之前曾表明，n-3 多不饱和脂肪酸（PUFA）通过增强磷脂氧化，部分促进结肠细胞凋亡，这是结肠癌风险的一个标志物。为了阐明调节体内氧化应激诱导细胞凋亡的机制，我们用含有 15%玉米油（富含 n-6PUFA）或 3.5%玉米油+11.5%鱼油（富含 n-3PUFA）的饮食喂养杂合 SOD2（Het）、Gpx4（Het）和转基因 Gpx4（Tg）小鼠 4 周。我们的数据表明：（i）遗传易感性氧化应激促进了小鼠结肠中的细胞凋亡（Gpx4（Het）> SOD2（Het）>Wt>Gpx4（Tg））；（ii）膳食 n-3PUFA 对 Gpx4（Het）和 SOD2（Het）小鼠细胞凋亡的诱导具有附加作用；（iii）膳食 n-3PUFA 通过将 Gpx4（Tg）氧化保护小鼠的细胞凋亡提高到野生型（Wt；对照）动物的水平，从而逆转了氧化保护表型。补充实验研究结肠线粒体生物能谱表明，与对照 CO 处理相比，FO 喂养的小鼠表现出明显（P<0.05）增加的呼吸诱导质子泄漏。这一发现与慢性氧化应激导致膜电位丧失一致，并支持 n-3PUFA 改变线粒体代谢活性，从而增强细胞凋亡和降低结肠癌风险的观点。
