Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China.
Eur J Pharmacol. 2016 Jun 15;781:164-72. doi: 10.1016/j.ejphar.2016.04.016. Epub 2016 Apr 12.
Metabolic stress induces autophagy as a protective mechanism in tumorigenesis and development. Conversely, excessive autophagy in nutrient-deprived cancer cells would be beneficial for cancer therapy. DT-13, the saponin monomer 13 of the Dwarf lilyturf tuber, inhibited tumor metastasis and angiogenesis in previous studies. However, there is scarcity of data regarding the effect of DT-13 on autophagy process. Here, we demonstrated that DT-13 induced autophagy in human cancer cell lines and caused significant cell apoptosis under nutrient starvation. We firstly showed that DT-13 increased the accumulation of GFP-LC3 puncta and induced the expression of LC3-II in a dose- and time-dependent manner. DT-13 also upregulated the expression of Beclin-1, Atg-3 and Atg-7, and induced autophagic flux in human gastric cancer BGC-823 cells. We next found that low-toxic concentrations of DT-13 significantly induced apoptosis under nutrient deprivation. We finally demonstrated that the PI3K/Akt/mTOR signal pathway was involved in the cytotoxic effect of DT-13. Our data indicated that DT-13 was a novel autophagy inducer and might be considered in future treatment of cancer.
代谢应激诱导自噬作为肿瘤发生和发展的一种保护机制。相反，营养缺乏的癌细胞中过度的自噬有利于癌症治疗。在之前的研究中，来自菝葜的甾体皂苷单体 13（DT-13）抑制肿瘤转移和血管生成。然而，关于 DT-13 对自噬过程影响的数据却很少。在这里，我们证明 DT-13 诱导人癌细胞系自噬，并在营养饥饿下导致显著的细胞凋亡。我们首先表明，DT-13 以剂量和时间依赖的方式增加 GFP-LC3 斑点的积累并诱导 LC3-II 的表达。DT-13 还上调了 Beclin-1、Atg-3 和 Atg-7 的表达，并诱导人胃癌 BGC-823 细胞中的自噬通量。我们接下来发现，低毒性浓度的 DT-13 在营养剥夺下显著诱导细胞凋亡。我们最后证明 PI3K/Akt/mTOR 信号通路参与了 DT-13 的细胞毒性作用。我们的数据表明 DT-13 是一种新型的自噬诱导剂，可能在未来的癌症治疗中得到考虑。
