Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through blocking beta-catenin and cyclooxygenase-2.
Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through blocking beta-catenin and cyclooxygenase-2.
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DOI：
10.1158/1535-7163.mct-09-0551
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发表时间：
2009-11
影响因子：
5.7
通讯作者：
Wu T
中科院分区：
文献类型：
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作者：
Lim K;Han C;Dai Y;Shen M;Wu T
肝细胞癌（Hepatocellular carcinoma，HCC）是一种常见的恶性肿瘤，死亡率高，目前尚无有效的化学预防或系统治疗方法。最近的证据表明，考克斯-2衍生的PGE 2和Wnt/β-catenin信号通路参与了肝癌的发生。我们报道了ω-3多不饱和脂肪酸，二十二碳六烯酸（DHA）和二十碳五烯酸（EPA），通过同时抑制考克斯-2和β-catenin抑制HCC生长。DHA和EPA处理导致三种人HCC细胞系（Hep 3B、Huh-7、HepG 2）中细胞活力的剂量依赖性降低，伴随PARP、半胱天冬酶-3和半胱天冬酶-9的裂解。相比之下，花生四烯酸（AA），ω-6 PUFA，没有表现出显着的影响。DHA和EPA处理引起GSK-3β的去磷酸化，从而激活GSK-3β，导致Hep 3B细胞中的β-连环蛋白降解。GSK 3-β抑制剂LiCl可部分阻止DHA诱导的β-catenin蛋白降解和细胞凋亡。此外，DHA诱导β-catenin/Axin/GSK-3β结合复合物的形成，这是β-catenin降解的平行机制。此外，DHA通过下调考克斯-2和上调考克斯-2拮抗剂15-羟基前列腺素脱氢酶（15-PGDH）抑制PGE 2信号传导。最后，将小鼠肝癌细胞（Hepa 1 -6）接种到表达秀丽隐杆线虫去饱和酶的Fat-1转基因小鼠体内时，肝癌的体内生长显着减少，该酶将ω-6转化为ω-3 PUFA。这些发现为ω-3 PUFAs用于人类HCC的化学预防和治疗提供了重要的临床前证据和分子见解。
Hepatocellular carcinoma (HCC) is a common human cancer with high mortality and currently there is no effective chemoprevention or systematic treatment. Recent evidence suggests that COX-2-derived PGE2 and Wnt/β-catenin signaling pathways are implicated in hepatocarcinogenesis. Here we report that ω-3 PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), inhibit HCC growth through simultaneously inhibition of COX-2 and β-catenin. DHA and EPA treatment resulted in a dose-dependent reduction of cell viability with cleavage of PARP, caspase-3 and caspase-9 in three human HCC cell lines (Hep3B, Huh-7, HepG2). In contrast, arachidonic acid (AA), a ω-6 PUFA, exhibited no significant effect. DHA and EPA treatment caused dephosphorylation and thus activation of GSK-3β, leading to β-catenin degradation in Hep3B cells. The GSK3-β inhibitor, LiCl, partially prevented DHA-induced β-catenin protein degradation and apoptosis. Additionally, DHA induced the formation of β-catenin/Axin/GSK-3β binding complex, which serves as a parallel mechanism for β-catenin degradation. Furthermore, DHA inhibited PGE2 signaling through downregulation of COX-2 and upregulation of the COX-2 antagonist, 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Finally, the growth of HCC in vivo was significantly reduced when mouse HCCs (Hepa1–6) were inoculated into the Fat-1 transgenic mice which express a Caenorhabditis elegans desaturase converting ω-6 to ω-3 PUFAs endogenously. These findings provide important preclinical evidence and molecular insight for utilization of ω-3 PUFAs for the chemoprevention and treatment of human HCC.