Laboratory of Biomanufacturing and Food Engineering, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China.
Molecules. 2022 Oct 29;27(21):7358. doi: 10.3390/molecules27217358.
Lung cancer, especially adenocarcinoma, is the second most occurring and highest fatality-causing cancer worldwide. Many natural anticancer compounds, such as sesquiterpene lactones (SLs), show promising anticancer properties. Herein, we examined Lactucin, an SL from the plant , for its cytotoxicity, apoptotic-inducing, cell cycle inhibiting capacity, and associated protein expression. We also constructed a biotinylated Lactucin probe to isolate interacting proteins and identified them. We found that Lactucin stops the proliferation of A549 and H2347 lung adenocarcinoma cell lines while not affecting normal lung cell MRC5. It also significantly inhibits the cell cycle at G/G stage and induces apoptosis. The western blot analysis shows that Lactucin downregulates the MAPK pathway, cyclin, and cyclin-dependent kinases, inhibiting DNA repair while upregulating p53, p21, Bax, PTEN, and downregulation of Bcl-2. An increased p53 in response to DNA damage upregulates p21, Bax, and PTEN. In an activity-based protein profiling (ABPP) analysis of A549 cell's protein lysate using a biotinylated Lactucin probe, we found that Lactucin binds PGM, PKM, and LDHA PDH, four critical enzymes in central carbon metabolism in cancer cells, limiting cancer cells in its growth; thus, Lactucin inhibits cancer cell proliferation by downregulating the MAPK and the Central Carbon Metabolism pathway.
肺癌，尤其是腺癌，是全球第二大高发和致死率最高的癌症。许多天然抗癌化合物，如倍半萜内酯（SLs），表现出有希望的抗癌特性。在这里，我们研究了来自植物的倍半萜内酯 Lactucin 的细胞毒性、诱导凋亡、细胞周期抑制能力及其相关蛋白表达。我们还构建了一个生物素化的 Lactucin 探针来分离相互作用的蛋白质并对其进行鉴定。我们发现 Lactucin 阻止了 A549 和 H2347 肺腺癌细胞系的增殖，而对正常肺细胞 MRC5 没有影响。它还显著抑制细胞周期在 G1 期，并诱导细胞凋亡。Western blot 分析表明，Lactucin 下调 MAPK 通路、细胞周期蛋白和细胞周期蛋白依赖性激酶，抑制 DNA 修复，同时上调 p53、p21、Bax、PTEN，并下调 Bcl-2。DNA 损伤引起的 p53 增加上调 p21、Bax 和 PTEN。在使用生物素化 Lactucin 探针对 A549 细胞蛋白裂解物进行的基于活性的蛋白质谱分析（ABPP）中，我们发现 Lactucin 与 PGM、PKM 和 LDHA PDH 结合，这四种酶是癌细胞中中央碳代谢的关键酶，限制了癌细胞的生长；因此，Lactucin 通过下调 MAPK 和中央碳代谢途径抑制癌细胞增殖。
