Metabonomics applied in exploring the antitumour mechanism of physapubenolide on hepatocellular carcinoma cells by targeting glycolysis through the Akt-p53 pathway.
Metabonomics applied in exploring the antitumour mechanism of physapubenolide on hepatocellular carcinoma cells by targeting glycolysis through the Akt-p53 pathway.
复制标题
DOI：
10.1038/srep29926
复制
发表时间：
2016-07-15
影响因子：
4.6
通讯作者：
Kong LY
中科院分区：
文献类型：
--
作者：
Ma T;Fan BY;Zhang C;Zhao HJ;Han C;Gao CY;Luo JG;Kong LY
代谢组学可用于识别潜在标记物并发现未来治疗干预的新靶点。在这里，我们开发了一种基于气相色谱-质谱（GC/MS）分析和主成分分析（PCA）的代谢组学方法的新应用，用于快速探索酸浆菌中分离的细胞毒性醉茄内酯（PB）的抗癌机制。 PB 在体外和体内抑制肝细胞癌细胞的增殖，并伴有凋亡相关的生化事件，包括 caspase-3/7/9 和 PARP 的裂解。代谢谱分析表明，PB 扰乱了代谢模式并显着降低了乳酸的产生。这表明糖酵解的抑制在PB诱导的抗肿瘤作用中发挥着重要作用，糖酵解相关基因和蛋白质表达的降低进一步支持了这一点。此外，观察到p53水平增加和p-Akt表达减少，并且在Akt cDNA或p53 siRNA存在下逆转减弱的糖酵解和增强的细胞凋亡。这些结果证实 PB 通过 Akt-p53 途径表现出抗癌活性。我们的研究不仅首次报道了PB的抗肿瘤机制，而且表明PB是一种有前景的癌症治疗药物，代谢组学方法为有效探索有前景的抗癌化合物的分子机制提供了新策略。
Metabolomics can be used to identify potential markers and discover new targets for future therapeutic interventions. Here, we developed a novel application of the metabonomics method based on gas chromatography-mass spectrometry (GC/MS) analysis and principal component analysis (PCA) for rapidly exploring the anticancer mechanism of physapubenolide (PB), a cytotoxic withanolide isolated from Physalis species. PB inhibited the proliferation of hepatocellular carcinoma cells in vitro and in vivo, accompanied by apoptosis-related biochemical events, including the cleavage of caspase-3/7/9 and PARP. Metabolic profiling analysis revealed that PB disturbed the metabolic pattern and significantly decreased lactate production. This suggests that the suppression of glycolysis plays an important role in the anti-tumour effects induced by PB, which is further supported by the decreased expression of glycolysis-related genes and proteins. Furthermore, the increased level of p53 and decreased expression of p-Akt were observed, and the attenuated glycolysis and enhanced apoptosis were reversed in the presence of Akt cDNA or p53 siRNA. These results confirm that PB exhibits anti-cancer activities through the Akt-p53 pathway. Our study not only reports for the first time the anti-tumour mechanism of PB, but also suggests that PB is a promising therapeutic agent for use in cancer treatments and that metabolomic approaches provide a new strategy to effectively explore the molecular mechanisms of promising anticancer compounds.