Autophagy inhibition enhances anthocyanin-induced apoptosis in hepatocellular carcinoma
Autophagy inhibition enhances anthocyanin-induced apoptosis in hepatocellular carcinoma
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DOI：
10.1158/1535-7163.mct-08-0361
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发表时间：
2008-08-01
影响因子：
5.7
通讯作者：
Tessitore, Luciana
中科院分区：
文献类型：
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作者：
Longo, Luigia;Platini, Francesca;Tessitore, Luciana
从宽叶连翘（Phillyrea latifolia L.）阿月浑子，和Rubia peregrina L.，研究了三种广泛分布于地中海地区的万年青灌木的抗氧化和抗癌活性。其中，紫丁香花色苷对H2 O2和1，1-二苯基-2-苦基-肼自由基的清除效果最好，可作为食品和医药产品中天然抗氧化剂的替代来源。在这里，我们还报告了花青素的一个新功能：诱导自噬，一个参与致癌作用的亚细胞周转过程。自噬的特征在于自噬诱导剂eIF 2 α的上调以及两种自噬抑制剂mTCR和Bcl-2的下调。这导致了LC 3-II（哺乳动物中的自噬体标记物）的表达增强，以及单丹酰尸胺掺入自溶酶体中。花青素诱导的自噬转变为细胞凋亡，如Bax，细胞色素c和caspase 3的激活，末端脱氧核苷酸转移酶介导的dUTP缺口末端标记阳性的碎片化细胞核，以及具有sub-G，DNA含量的细胞所示，这被z-VAD阻止。抑制自噬的3-甲基腺嘌呤或Atg 5小干扰RNA增强花青素触发的细胞凋亡。这提供了自噬作为肝癌细胞对抗花青素诱导的细胞凋亡的存活机制的证据，以及自噬抑制剂与饮食化学预防剂组合使用的基本原理。
Anthocyanins extracted from the berries of Phillyrea latifolia L., Pistacia lentiscus L., and Rubia peregrina L., three evergreen shrubs widely distributed in the Mediterranean area, were examined for their antioxidant and anticancer activity. The P. lentiscus anthocyanins showed the highest H2O2 and 1,1-diphenyl-2-picryl-hydrazil radical scavenging effects, indicating that these compounds can be considered as an alternative source of natural antioxidants for food and pharmaceutical products. Here, we also report a novel function of anthocyanins: the induction of autophagy, a process of subcellular turnover involved in carcinogenesis. Autophagy was characterized by the up-regulation of eIF2 alpha, an autophagy inducer, and down-regulation of mTCR and Bcl-2, two autophagy inhibitors. This led to the enhanced expression of LC3-II, an autophagosome marker in mammals, and monodansylcadaverine incorporation into autolysosomes. Anthocyanin-induced autophagy switched to apoptosis, as shown by the activation of Bax, cytochrome c and caspase 3, terminal deoxynucleotide transferase-mediated dUTP nick-end labeling-positive fragmented nuclei, and cells with sub-G, DNA content, which were prevented by z-VAD. Inhibition of autophagy by either 3-methyladenine or Atg5 small interfering RNA enhanced anthocyanin-triggered apoptosis. This provided evidence that autophagy functions as a survival mechanism in liver cancer cells against anthocyanin-induced apoptosis and a rationale for the use of autophagy inhibitors in combination with dietary chemopreventive agents.