School of Life and Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Hainan Key Laboratory for Sustainable Utilization of Tropical Bioresources, College of Tropical Crops, Hainan University, Haikou, 570228, China; Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; Institute of Molecular Rhythm and Metabolism, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
Biochem Biophys Res Commun. 2021 Apr 2;547:52-58. doi: 10.1016/j.bbrc.2021.01.112. Epub 2021 Feb 13.
Natural products are useful tools for biological mechanism research and drug discovery. Due to the excellent tumor cell growth inhibitory profile and sub-nanomolar potency, Coibamide A (CA), an N-methyl-stabilized depsipeptide isolated from marine cyanobacterium, has been considered as a promising lead compound for cancer treatment. However, the molecular anti-cancer mechanism of the action of CA remains unclear. Here, we showed that CA treatment induced caspase-independent cell death in breast cancer cells. CA treatment also led to severe lysosome defects, which was ascribed to the impaired glycosylation of lysosome membrane protein LAMP1 and LAMP2. As a consequence, the autophagosome-lysosome fusion was blocked upon CA treatment. In addition, we presented evidence that this autophagy defect partially contributed to the CA treatment-induced tumor cell death. Together, our work uncovers a novel mechanism underlying the anti-cancer action of CA, which will promote its further application for cancer therapy.
天然产物是研究生物机制和发现药物的有用工具。由于具有优异的肿瘤细胞生长抑制作用和亚纳摩尔效力，从海洋蓝藻中分离得到的 N-甲基稳定的脱肽 Coibamide A（CA）被认为是一种有前途的癌症治疗先导化合物。然而，CA 的分子抗癌作用机制尚不清楚。在这里，我们表明 CA 处理诱导乳腺癌细胞中的 caspase 非依赖性细胞死亡。CA 处理还导致严重的溶酶体缺陷，这归因于溶酶体膜蛋白 LAMP1 和 LAMP2 的糖基化受损。结果，自噬体-溶酶体融合在 CA 处理时受阻。此外，我们提供的证据表明，这种自噬缺陷部分导致了 CA 处理诱导的肿瘤细胞死亡。总之，我们的工作揭示了 CA 抗癌作用的新机制，这将促进其在癌症治疗中的进一步应用。
