Nutrition and Cancer Biology Laboratory, Jean-Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Room 514, Boston, MA 02111.
Cancer Prev Res (Phila). 2013 Dec;6(12):1304-16. doi: 10.1158/1940-6207.CAPR-13-0178. Epub 2013 Oct 1.
Obesity is associated with increased risk in hepatocellular carcinoma (HCC) development and mortality. An important disease control strategy is the prevention of obesity-related hepatic inflammation and tumorigenesis by dietary means. Here, we report that apo-10'-lycopenoic acid (APO10LA), a cleavage metabolite of lycopene at its 9',10'-double bond by carotene-9',10'-oxygenase, functions as an effective chemopreventative agent against hepatic tumorigenesis and inflammation. APO10LA treatment on human liver THLE-2 and HuH7 cells dose dependently inhibited cell growth and upregulated sirtuin 1 (SIRT1), a NAD(+)-dependent protein deacetylase that may suppress hepatic carcinogenesis. This observed SIRT1 induction was associated with decreased cyclin D1 protein, increased cyclin-dependent kinase inhibitor p21 protein expression, and induced apoptosis. APO10LA supplementation (10 mg/kg diet) for 24 weeks significantly reduced diethylnitrosamine-initiated, high fat diet (HFD)-promoted hepatic tumorigenesis (50% reduction in tumor multiplicity; 65% in volume) and lung tumor incidence (85% reduction) in C57Bl/6J mice. The chemopreventative effects of APO10LA were associated with increased hepatic SIRT1 protein and deacetylation of SIRT1 targets, as well as with decreased caspase-1 activation and SIRT1 protein cleavage. APO10LA supplementation in diet improved glucose intolerance and reduced hepatic inflammation [decreased inflammatory foci, TNFα, interleukin (IL)-6, NF-κB p65 protein expression, and STAT3 activation] in HFD-fed mice. Furthermore, APO10LA suppressed Akt activation, cyclin D1 gene, and protein expression and promoted PARP protein cleavage in transformed cells within liver tumors. Taken together, these data indicate that APO10LA can effectively inhibit HFD-promoted hepatic tumorigenesis by stimulating SIRT1 signaling while reducing hepatic inflammation.
肥胖与肝细胞癌 (HCC) 发展和死亡率增加有关。一个重要的疾病控制策略是通过饮食来预防肥胖相关的肝炎症和肿瘤发生。在这里，我们报告说，apo-10'-lycopenoic 酸 (APO10LA)，一种在其 9'，10'-双键处由类胡萝卜素 9'，10'-加氧酶切割的番茄红素代谢物，作为一种有效的化学预防剂，可抑制肝肿瘤发生和炎症。APO10LA 处理人肝 THLE-2 和 HuH7 细胞呈剂量依赖性地抑制细胞生长并上调 SIRT1（一种 NAD(+)依赖性蛋白去乙酰化酶，可能抑制肝致癌作用）。观察到的 SIRT1 诱导与细胞周期蛋白 D1 蛋白减少、细胞周期蛋白依赖性激酶抑制剂 p21 蛋白表达增加和诱导细胞凋亡有关。APO10LA 补充剂（饮食 10mg/kg）24 周显著降低二乙基亚硝胺诱导的高脂肪饮食（HFD）促进的肝肿瘤发生（肿瘤多发性降低 50%；体积降低 65%）和肺癌发病率（降低 85%）在 C57Bl/6J 小鼠中。APO10LA 的化学预防作用与增加肝 SIRT1 蛋白和 SIRT1 靶标的去乙酰化有关，还与 caspase-1 激活和 SIRT1 蛋白切割减少有关。APO10LA 补充饮食可改善葡萄糖不耐受并减少 HFD 喂养小鼠的肝炎症[减少炎症灶、TNFα、白细胞介素 (IL)-6、NF-κB p65 蛋白表达和 STAT3 激活]。此外，APO10LA 抑制 Akt 激活、细胞周期蛋白 D1 基因和蛋白表达，并在肝肿瘤内转化细胞中促进 PARP 蛋白切割。综上所述，这些数据表明 APO10LA 可通过刺激 SIRT1 信号通路同时减少肝炎症来有效抑制 HFD 促进的肝肿瘤发生。
