4.6 Article

Coibamide A kills cancer cells through inhibiting autophagy

期刊

出版社

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2021.01.112

关键词

Coibamide a; LAMP protein Glycosylation; Autophagy mediated cell death

资金

  1. National Natural Science Foundation of China [21672254, 31671397, 12027812, 21778068]
  2. Shenzhen Science and Technology Innovation Commission [JCYJ20170818153538196, JCYJ20170818162642882, JCYJ20200109114608075]

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Coibamide A is a promising lead compound for cancer treatment due to its excellent tumor cell growth inhibitory profile and sub-nanomolar potency. It induces caspase-independent cell death and severe lysosome defects, blocking autophagosomelysosome fusion and leading to tumor cell death. These findings provide novel insights into the anti-cancer mechanism of action of Coibamide A.
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 autophagosomelysosome 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. (c) 2021 Elsevier Inc. All rights reserved.

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