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Callyspongiolide kills cells by inducing mitochondrial dysfunction via cellular iron depletion

The highly cytotoxic marine natural product callyspongiolide holds great promise as a warhead of antibody-drug conjugate in cancer therapeutics; however, the mechanism underlying its cytotoxicity remains unclear. To elucidate how callyspongiolide kills cells, we employed label-free target identifica...

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Autores principales: Ha, Jaeyoung, Park, Seung Bum
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460830/
https://www.ncbi.nlm.nih.gov/pubmed/34556786
http://dx.doi.org/10.1038/s42003-021-02643-8
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author Ha, Jaeyoung
Park, Seung Bum
author_facet Ha, Jaeyoung
Park, Seung Bum
author_sort Ha, Jaeyoung
collection PubMed
description The highly cytotoxic marine natural product callyspongiolide holds great promise as a warhead of antibody-drug conjugate in cancer therapeutics; however, the mechanism underlying its cytotoxicity remains unclear. To elucidate how callyspongiolide kills cells, we employed label-free target identification with thermal stability-shift-based fluorescence difference in two-dimensional (2-D) gel electrophoresis (TS-FITGE), which allowed observation of a unique phenomenon of protein-spot separation on 2-D gels upon treatment with callyspongiolide at increasing temperatures. During our exploration of what proteins were associated with this phenomenon as well as why it happens, we found that callyspongiolide induces mitochondrial/lysosomal dysfunction and autophagy inhibition. Moreover, molecular biology studies revealed that callyspongiolide causes lysosomal dysfunction, which induces cellular iron depletion and leads to mitochondrial dysfunction and subsequent cytotoxicity. Notably, these effects were rescued through iron supplementation. Although our approach was unable to reveal the direct protein targets of callyspongiolide, unique phenomena observed only by TS-FITGE provided critical insight into the mechanism of action of callyspongiolide and specifically its cytotoxic activity via induction of mitochondrial dysfunction through cellular iron depletion caused by lysosomal deacidification, which occurred independent of known programmed cell death pathways.
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spelling pubmed-84608302021-10-22 Callyspongiolide kills cells by inducing mitochondrial dysfunction via cellular iron depletion Ha, Jaeyoung Park, Seung Bum Commun Biol Article The highly cytotoxic marine natural product callyspongiolide holds great promise as a warhead of antibody-drug conjugate in cancer therapeutics; however, the mechanism underlying its cytotoxicity remains unclear. To elucidate how callyspongiolide kills cells, we employed label-free target identification with thermal stability-shift-based fluorescence difference in two-dimensional (2-D) gel electrophoresis (TS-FITGE), which allowed observation of a unique phenomenon of protein-spot separation on 2-D gels upon treatment with callyspongiolide at increasing temperatures. During our exploration of what proteins were associated with this phenomenon as well as why it happens, we found that callyspongiolide induces mitochondrial/lysosomal dysfunction and autophagy inhibition. Moreover, molecular biology studies revealed that callyspongiolide causes lysosomal dysfunction, which induces cellular iron depletion and leads to mitochondrial dysfunction and subsequent cytotoxicity. Notably, these effects were rescued through iron supplementation. Although our approach was unable to reveal the direct protein targets of callyspongiolide, unique phenomena observed only by TS-FITGE provided critical insight into the mechanism of action of callyspongiolide and specifically its cytotoxic activity via induction of mitochondrial dysfunction through cellular iron depletion caused by lysosomal deacidification, which occurred independent of known programmed cell death pathways. Nature Publishing Group UK 2021-09-23 /pmc/articles/PMC8460830/ /pubmed/34556786 http://dx.doi.org/10.1038/s42003-021-02643-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Ha, Jaeyoung
Park, Seung Bum
Callyspongiolide kills cells by inducing mitochondrial dysfunction via cellular iron depletion
title Callyspongiolide kills cells by inducing mitochondrial dysfunction via cellular iron depletion
title_full Callyspongiolide kills cells by inducing mitochondrial dysfunction via cellular iron depletion
title_fullStr Callyspongiolide kills cells by inducing mitochondrial dysfunction via cellular iron depletion
title_full_unstemmed Callyspongiolide kills cells by inducing mitochondrial dysfunction via cellular iron depletion
title_short Callyspongiolide kills cells by inducing mitochondrial dysfunction via cellular iron depletion
title_sort callyspongiolide kills cells by inducing mitochondrial dysfunction via cellular iron depletion
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460830/
https://www.ncbi.nlm.nih.gov/pubmed/34556786
http://dx.doi.org/10.1038/s42003-021-02643-8
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