Lycorine Promotes Autophagy and Apoptosis via TCRP1/Akt/mTOR Axis Inactivation in Human Hepatocellular Carcinoma
Lycorine Promotes Autophagy and Apoptosis via TCRP1/Akt/mTOR Axis Inactivation in Human Hepatocellular Carcinoma
复制标题
石蒜碱通过 TCRP1/Akt/mTOR 轴失活促进人肝细胞癌中的自噬和细胞凋亡
DOI：
10.1158/1535-7163.mct-17-0498
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发表时间：
2017-12-01
影响因子：
5.7
通讯作者：
Wang, Tao
中科院分区：
文献类型：
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作者：
Yu, Haiyang;Qiu, Yuling;Wang, Tao
石蒜碱是一种多功能生物活性化合物，具有潜在的抗癌活性。然而，人们对潜在的机制知之甚少。在本研究中，我们发现石蒜碱在体外和体内都能显著诱导肝癌细胞的凋亡和自噬能力。用特异性自噬抑制剂（3-甲基腺嘌呤/巴弗洛霉素A1）处理或通过siRNA敲低LC-3B/Atg 5通过促进自噬向凋亡的转换而显著增强凋亡性细胞死亡效应。分子验证机制表明石蒜碱诱导的肝癌细胞凋亡和自噬与舌癌耐药相关蛋白1（TCRP 1）蛋白水平降低相关，我们进一步发现抑制TCRP 1降低Akt磷酸化水平并抑制Akt/mTOR信号传导。最后，石蒜碱诱导的细胞凋亡和自噬抑制异种肝细胞肿瘤的生长，而没有显着的毒性。我们的研究结果阐明了石蒜碱通过TCRP 1/Akt/mTOR途径促进肝癌细胞凋亡和自噬的新分子机制。石蒜碱可能是一种潜在的治疗肝癌的药物。Mol Cancer Ther; 16（12）; 2711-23.©2017 AACR.
Lycorine is a multifunctional bioactive compound, and it possesses potential anticancer activities. However, little is known about the underlying mechanism. In this research, we have found that lycorine significantly induces the apoptotic and autophagic capacities of hepatocellular carcinoma (HCC) cells in vitro and in vivo. Treatment with specific autophagy inhibitor (3-methyladenine/Bafilomycin A1) or knockdown of LC-3B/Atg5 by siRNA drastically enhances the apoptotic cell death effect by facilitating the switch from autophagy to apoptosis. Molecular validation mechanistically demonstrates that lycorine-induced apoptosis and autophagy in HCC cells is associated with decreased protein levels of tongue cancer resistance–associated protein 1 (TCRP1), and we further find that inhibition of TCRP1 decreases phosphorylation level of Akt and represses Akt/mTOR signaling. Finally, lycorine-induced apoptosis and autophagy suppress the growth of xenograft hepatocellular tumors without remarkable toxicity. Our results elucidate a novel molecular mechanism whereby lycorine promotes apoptosis and autophagy through the TCRP1/Akt/mTOR pathway in HCC. Our results reveal that lycorine might be a potential therapeutic agent for the treatment of HCC. Mol Cancer Ther; 16(12); 2711–23. ©2017 AACR.