Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
School of Pharmacy, Tianjin Medical University, Tianjin, China.
Mol Cancer Ther. 2017 Dec;16(12):2711-2723. doi: 10.1158/1535-7163.MCT-17-0498. Epub 2017 Sep 28.
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 and 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. .
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，其潜在的作用机制知之甚少。在这项研究中，我们发现石蒜碱能显著诱导肝癌（HCC）细胞的凋亡和自噬作用，并且用特异性自噬抑制剂（3-甲基腺嘌呤/巴弗洛霉素 A1）或 LC-3B/Atg5 的 siRNA 敲低处理能明显增强细胞凋亡作用，从而促进自噬向凋亡的转变。分子验证机制表明，石蒜碱诱导 HCC 细胞的凋亡和自噬与舌癌细胞耐药相关蛋白 1（TCRP1）的蛋白水平降低有关，我们进一步发现抑制 TCRP1 能降低 Akt 的磷酸化水平并抑制 Akt/mTOR 信号通路。最后，石蒜碱诱导的凋亡和自噬能抑制异种移植肝癌肿瘤的生长，而没有明显的毒性。我们的研究结果阐明了石蒜碱通过 HCC 中的 TCRP1/Akt/mTOR 通路促进凋亡和自噬的新分子机制。我们的结果表明，石蒜碱可能是治疗 HCC 的一种潜在治疗药物。
