Coibamide A kills cancer cells through inhibiting autophagy

• Published in: Biochemical and biophysical research communications 2021-04, Vol.547, p.52-58
• Main Authors: Shi, Wenli, Lu, Danyi, Wu, Chunlei, Li, Meiqing, Ding, Zhihao, Li, Yanyan, Chen, Binghua, Lin, Xian, Su, Wu, Shao, Ximing, Xia, Zhihui, Fang, Lijing, Liu, Ke, Li, Hongchang
• Format: Article
• Language: English
• Subjects: Autophagy mediated cell death; Coibamide a; LAMP protein Glycosylation
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2021.01.112

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. •CA treatment induced caspase-independent cell death in breast cancer cells.•CA treatment led to severe lysosome defects by impairing glycosylation of lysosome membrane protein LAMP1 and LAMP2.•Block of autophagosome-lysosome fusion by CA partially contributed to CA-induced caspase-independent cell death in human breast cancer cells.