Polyphyllin I activates AMPK to suppress the growth of non-small-cell lung cancer via induction of autophagy
Polyphyllin I activates AMPK to suppress the growth of non-small-cell lung cancer via induction of autophagy
复制标题
Polyphyllin I 激活 AMPK 通过诱导自噬抑制非小细胞肺癌的生长
DOI：
10.1016/j.abb.2020.108285
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发表时间：
2020
影响因子：
3.9
通讯作者：
Liu Ying
中科院分区：
文献类型：
--
作者：
Wu Yezi;Si Yuan;Xiang Yuchen;Zhou Tong;Liu Xuewen;Wu Mingwei;Li Wenjuan;Zhang Te;Xiang Ke;Zhang Liang;Zhao Huzi;Liu Ying
从巴黎多叶属植物的根茎中提取的多叶磷脂I （PPI）是一种生物活性成分，对几种类型的癌症具有细胞毒性。本研究旨在探讨PPI是否能预防非小细胞肺癌（NSCLC）的生长，并探讨其分子机制。amp活化蛋白激酶（AMPK）在不同组织中参与了自噬的激活。在培养的人非小细胞肺癌细胞系中，PPI通过激活AMPK，然后以浓度依赖的方式抑制mTOR信号传导，诱导自噬。此外，PPI诱导的自噬激活被AMPK抑制剂化合物c逆转。计算对接表明，PPI直接与AMPK的变构药物和代谢位点相互作用，稳定了AMPK的激活。微尺度热电泳和药物亲和性靶向稳定性（dart）实验进一步证实了PPI与AMPK之间的高亲和性。体内研究表明，PPI抑制了非小细胞肺癌的生长，增加了从小鼠非小细胞肺癌异种移植模型分离的肿瘤中LC3-II和磷酸化AMPK的水平。此外，PPI在大鼠体内表现出良好的药代动力学。综上所述，PPI作为AMPK的直接激活剂，诱导细胞自噬，抑制NSCLC细胞的生长。在未来，PPI治疗应应用于非小细胞肺癌患者。
Polyphyllin I (PPI), a bioactive constituent extracted from the rhizomes ofParis polyphylla, is cytotoxic to several cancer types. This study was designed to explore whether PPI prevents non-small-cell lung cancer (NSCLC) growth and to investigate the molecular mechanism. AMP-activated protein kinase (AMPK) has been implicated in the activation of autophagy in distinct tissues. In cultured human NSCLC cell lines, PPI induces autophagy by activating AMPK and then inhibiting mTOR signaling in a concentration-dependent manner. Furthermore, the activation of autophagy induced by PPI was reversed by the AMPK inhibitor compound C. Computational docking showed that PPI directly interacted with the allosteric drug and metabolite site of AMPK to stabilize its activation. Microscale thermophoresis and Drug Affinity Responsive Targeting Stability (DARTS) assay further confirmed the high affinity between PPI and AMPK.In vivostudies indicated that PPI suppressed the growth of NSCLC and increased the levels of LC3-II and phosphorylated AMPK in tumors isolated from a xenograft model of NSCLC in mice. Moreover, PPI exhibited favorable pharmacokinetics in rats. In summary, PPI conclusively acts as a direct AMPK activator to induce cell autophagy which inhibits the growth of NSCLC cells. In the future, PPI therapy should be applied to treat patients with NSCLC.