Coibamide A kills cancer cells through inhibiting autophagy.

Affiliation

Shi W(1), Lu D(2), Wu C(3), Li M(4), Ding Z(3), Li Y(4), Chen B(4), Lin X(3), Su W(3), Shao X(3), Xia Z(5), Fang L(6), Liu K(7), Li H(8).
Author information:
(1)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.
(2)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.
(3)Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
(4)Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
(5)Hainan Key Laboratory for Sustainable Utilization of Tropical Bioresources, College of Tropical Crops, Hainan University, Haikou, 570228, China.
(6)Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China. Electronic address: [Email]
(7)Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China. Electronic address: [Email]
(8)Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China. Electronic address: [Email]

Abstract

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.