乙类肝素B通过肝癌中的ROS / p53信号通路诱导线粒体和溶酶体功能障碍，导致凋亡而非自噬细胞死亡,BIOCHEMICAL PHARMACOLOGY

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乙类肝素B通过肝癌中的ROS / p53信号通路诱导线粒体和溶酶体功能障碍，导致凋亡而非自噬细胞死亡
BIOCHEMICAL PHARMACOLOGY ( IF 5.3 ) Pub Date : 2017-10-01 , DOI: 10.1016/j.bcp.2017.06.134
Ya-di Geng , Chao Zhang , Jian-li Lei , Pei Yu , Yuan-zheng Xia , Hao Zhang , Lei Yang , Ling-yi Kong

摘要Walsuronoid B是从芥末Walsura提取的柠檬苦素类化合物。先前的研究表明柠檬苦素类化合物具有抗癌潜力，尽管这种活性的分子机制仍然难以捉摸。在这项研究中，我们首次证明了类鲸蜡素B抑制几种人类癌症细胞系中的细胞增殖。选择肝癌细胞（HepG2和Bel‐7402）是因为它们对类胡萝卜素B具有很高的敏感性。类胡萝卜素B通过G2 / M期阻滞和细胞凋亡诱导细胞死亡，并通过抑制mTOR信号传导诱导自噬体的积累，这可作为一种抗癌药物。细胞存活机制并防止细胞死亡。我们进一步检查了分子机制，发现由类鲸类B诱导的线粒体和溶酶体功能障碍，而不是内质网导致其细胞死亡。鲸类类胡萝卜素B增强了过氧化氢，一氧化氮和超氧阴离子自由基的产生，导致活性氧（ROS）含量升高。此外，由类Walsuronoid B诱导的ROS上调了p53水平。相反，p53刺激了ROS。这些结果表明，ROS和p53相互促进彼此的产生，并协同诱导肝癌细胞死亡。我们发现，ROS和p53的诱导显着触发了G2 / M期阻滞以及线粒体和溶酶体凋亡。最后，类Walsuronoid B在体内抑制肿瘤生长，几乎没有副作用。总之，

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Walsuronoid B induces mitochondrial and lysosomal dysfunction leading to apoptotic rather than autophagic cell death via ROS/p53 signaling pathways in liver cancer

ABSTRACT Walsuronoid B is a limonoid compound extracted from Walsura robusta. Previous studies have shown that limonoid compounds possess anti‐cancer potential, although the molecular mechanism of this activity remains elusive. In this study, we demonstrated for the first time that walsuronoid B inhibited cell proliferation in several human cancer lines. Liver cancer cells (HepG2 and Bel‐7402) were chosen for their high sensitivity to walsuronoid B. Walsuronoid B induced cell death through G2/M phase arrest and apoptosis and induced the accumulation of autophagosomes through the suppression of mTOR signaling, which serves as a cell survival mechanism and prevents cell death. We further examined the molecular mechanisms and found that walsuronoid B‐induced dysfunction of the mitochondria and lysosomes rather than the endoplasmic reticulum contributed to its cell death effect. Walsuronoid B enhanced the generation of hydrogen peroxide, nitric oxide and superoxide anion radical, resulting in elevated levels of reactive oxygen species (ROS). In addition, ROS induced by walsuronoid B upregulated p53 levels; conversely, p53 stimulated ROS. These results suggested that ROS and p53 reciprocally promoted each other's production and cooperated to induce liver cancer cell death. We found that the induction of ROS and p53 significantly triggered G2/M phase arrest and mitochondrial and lysosomal apoptosis. Finally, walsuronoid B suppressed tumor growth in vivo with few side effects. In summary, our findings demonstrated that walsuronoid B caused G2/M phase arrest and induced mitochondrial and lysosomal apoptosis through the ROS/p53 signaling pathway in human liver cancer cells in vitro and in vivo.

更新日期：2017-10-01

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