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Mitochondrial dysfunction induced by callyspongiolide promotes autophagy-dependent cell death

Callyspongiolide is a marine macrolide known to induce caspase-independent cancer cell death. While its toxic effects have been known, the mechanism leading to cell death is yet to be identified. We report that Callyspongiolide R form at C-21 (cally2R) causes mitochondrial dysfunction by inhibiting...

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Autores principales: Lee, Soohyun, Jeong, Yoonjeong, Roe, Jae-Seok, Huh, Hoyoung, Paik, Sang Hoon, Song, Jaewhan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Korean Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093938/
https://www.ncbi.nlm.nih.gov/pubmed/33792534
http://dx.doi.org/10.5483/BMBRep.2021.54.4.037
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author Lee, Soohyun
Jeong, Yoonjeong
Roe, Jae-Seok
Huh, Hoyoung
Paik, Sang Hoon
Song, Jaewhan
author_facet Lee, Soohyun
Jeong, Yoonjeong
Roe, Jae-Seok
Huh, Hoyoung
Paik, Sang Hoon
Song, Jaewhan
author_sort Lee, Soohyun
collection PubMed
description Callyspongiolide is a marine macrolide known to induce caspase-independent cancer cell death. While its toxic effects have been known, the mechanism leading to cell death is yet to be identified. We report that Callyspongiolide R form at C-21 (cally2R) causes mitochondrial dysfunction by inhibiting mitochondrial complex I or II, leading to a disruption of mitochondrial membrane potential and a deprivation of cellular energy. Subsequently, we observed, using electron microscopy, a drastic formation of autophagosome and mitophagy. Supporting these data, LC3, an autophagosome marker, was shown to co-localize with LAMP2, a lysosomal protein, showing autolysosome formation. RNA sequencing results indicated the induction of hypoxia and blocking of EGF-dependent pathways, which could be caused by induction of autophagy. Furthermore, mTOR and AKT pathways preventing autophagy were repressed while AMPK was upregulated, supporting autophagosome progress. Finally, the combination of cally2R with known anti-cancer drugs, such as gefitinib, sorafenib, and rapamycin, led to synergistic cell death, implicating potential therapeutic applications of callyspongiolide for future treatments.
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spelling pubmed-80939382021-05-13 Mitochondrial dysfunction induced by callyspongiolide promotes autophagy-dependent cell death Lee, Soohyun Jeong, Yoonjeong Roe, Jae-Seok Huh, Hoyoung Paik, Sang Hoon Song, Jaewhan BMB Rep Article Callyspongiolide is a marine macrolide known to induce caspase-independent cancer cell death. While its toxic effects have been known, the mechanism leading to cell death is yet to be identified. We report that Callyspongiolide R form at C-21 (cally2R) causes mitochondrial dysfunction by inhibiting mitochondrial complex I or II, leading to a disruption of mitochondrial membrane potential and a deprivation of cellular energy. Subsequently, we observed, using electron microscopy, a drastic formation of autophagosome and mitophagy. Supporting these data, LC3, an autophagosome marker, was shown to co-localize with LAMP2, a lysosomal protein, showing autolysosome formation. RNA sequencing results indicated the induction of hypoxia and blocking of EGF-dependent pathways, which could be caused by induction of autophagy. Furthermore, mTOR and AKT pathways preventing autophagy were repressed while AMPK was upregulated, supporting autophagosome progress. Finally, the combination of cally2R with known anti-cancer drugs, such as gefitinib, sorafenib, and rapamycin, led to synergistic cell death, implicating potential therapeutic applications of callyspongiolide for future treatments. Korean Society for Biochemistry and Molecular Biology 2021-04-30 2021-04-30 /pmc/articles/PMC8093938/ /pubmed/33792534 http://dx.doi.org/10.5483/BMBRep.2021.54.4.037 Text en Copyright © 2021 by the The Korean Society for Biochemistry and Molecular Biology https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0 (https://creativecommons.org/licenses/by-nc/4.0/) ) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Article
Lee, Soohyun
Jeong, Yoonjeong
Roe, Jae-Seok
Huh, Hoyoung
Paik, Sang Hoon
Song, Jaewhan
Mitochondrial dysfunction induced by callyspongiolide promotes autophagy-dependent cell death
title Mitochondrial dysfunction induced by callyspongiolide promotes autophagy-dependent cell death
title_full Mitochondrial dysfunction induced by callyspongiolide promotes autophagy-dependent cell death
title_fullStr Mitochondrial dysfunction induced by callyspongiolide promotes autophagy-dependent cell death
title_full_unstemmed Mitochondrial dysfunction induced by callyspongiolide promotes autophagy-dependent cell death
title_short Mitochondrial dysfunction induced by callyspongiolide promotes autophagy-dependent cell death
title_sort mitochondrial dysfunction induced by callyspongiolide promotes autophagy-dependent cell death
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093938/
https://www.ncbi.nlm.nih.gov/pubmed/33792534
http://dx.doi.org/10.5483/BMBRep.2021.54.4.037
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