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Toosendanin, a novel potent vacuolar-type H(+)-translocating ATPase inhibitor, sensitizes cancer cells to chemotherapy by blocking protective autophagy
Macroautophagy/autophagy is the process of self-digestion through the lysosomes; it disassembles unnecessary or dysfunctional long-lived proteins and damaged organelles for the recycling of biomacromolecules. Unfortunately, cancer cells can hijack this mechanism to survive under metabolic stress or...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9066121/ https://www.ncbi.nlm.nih.gov/pubmed/35541921 http://dx.doi.org/10.7150/ijbs.71041 |
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author | Dong, Yu Zhu, Guoyuan Wang, Sheng-Fang Keon, Kristine A. Rubinstein, John L. Zeng, Si-Xin Zhang, Shuang Chen, Qiu-Ling Fu, Jing Li, Min Shen, Han-Ming Lu, Jin-Jian Chen, Xiu-Ping Lu, Jia-Hong |
author_facet | Dong, Yu Zhu, Guoyuan Wang, Sheng-Fang Keon, Kristine A. Rubinstein, John L. Zeng, Si-Xin Zhang, Shuang Chen, Qiu-Ling Fu, Jing Li, Min Shen, Han-Ming Lu, Jin-Jian Chen, Xiu-Ping Lu, Jia-Hong |
author_sort | Dong, Yu |
collection | PubMed |
description | Macroautophagy/autophagy is the process of self-digestion through the lysosomes; it disassembles unnecessary or dysfunctional long-lived proteins and damaged organelles for the recycling of biomacromolecules. Unfortunately, cancer cells can hijack this mechanism to survive under metabolic stress or develop drug resistance during chemotherapy. Increasing evidence indicates that the combination of autophagy inhibition and chemotherapy is a promising cancer treatment strategy. However, effective autophagy inhibitors with satisfied potency, bioavailability, and clearly-defined drug targets are still rare. Here, we report the identification of a potent autophagy inhibitor toosendanin which can effectively block autophagosome maturation, causing the accumulation of autophagy substrates in multiple cancer cells. Toosendanin did not inhibit the fusion process between autophagosome and lysosome but elevated lysosomal pH and impaired lysosomal enzymes activity. Using rat liver lysosome fraction and purified yeast V-ATPase, we found that toosendanin directly inhibited V-ATPase activity. By applying cellular thermal shift assay (CETSA), immunoprecipitation-coupled LC-MS/MS analysis, and biotin-toosendanin pull-down assay, we confirmed the direct binding between toosendanin and V-ATPase. Furthermore, toosendanin blocked chemotherapy-induced protective autophagy in cultured cancer cells and xenograft tumor tissues to significantly enhance anti-cancer activity. These results suggest that toosendanin has the potential to be developed into an anti-cancer drug by blocking chemotherapy-induced protective autophagy. |
format | Online Article Text |
id | pubmed-9066121 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-90661212022-05-09 Toosendanin, a novel potent vacuolar-type H(+)-translocating ATPase inhibitor, sensitizes cancer cells to chemotherapy by blocking protective autophagy Dong, Yu Zhu, Guoyuan Wang, Sheng-Fang Keon, Kristine A. Rubinstein, John L. Zeng, Si-Xin Zhang, Shuang Chen, Qiu-Ling Fu, Jing Li, Min Shen, Han-Ming Lu, Jin-Jian Chen, Xiu-Ping Lu, Jia-Hong Int J Biol Sci Research Paper Macroautophagy/autophagy is the process of self-digestion through the lysosomes; it disassembles unnecessary or dysfunctional long-lived proteins and damaged organelles for the recycling of biomacromolecules. Unfortunately, cancer cells can hijack this mechanism to survive under metabolic stress or develop drug resistance during chemotherapy. Increasing evidence indicates that the combination of autophagy inhibition and chemotherapy is a promising cancer treatment strategy. However, effective autophagy inhibitors with satisfied potency, bioavailability, and clearly-defined drug targets are still rare. Here, we report the identification of a potent autophagy inhibitor toosendanin which can effectively block autophagosome maturation, causing the accumulation of autophagy substrates in multiple cancer cells. Toosendanin did not inhibit the fusion process between autophagosome and lysosome but elevated lysosomal pH and impaired lysosomal enzymes activity. Using rat liver lysosome fraction and purified yeast V-ATPase, we found that toosendanin directly inhibited V-ATPase activity. By applying cellular thermal shift assay (CETSA), immunoprecipitation-coupled LC-MS/MS analysis, and biotin-toosendanin pull-down assay, we confirmed the direct binding between toosendanin and V-ATPase. Furthermore, toosendanin blocked chemotherapy-induced protective autophagy in cultured cancer cells and xenograft tumor tissues to significantly enhance anti-cancer activity. These results suggest that toosendanin has the potential to be developed into an anti-cancer drug by blocking chemotherapy-induced protective autophagy. Ivyspring International Publisher 2022-03-28 /pmc/articles/PMC9066121/ /pubmed/35541921 http://dx.doi.org/10.7150/ijbs.71041 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Dong, Yu Zhu, Guoyuan Wang, Sheng-Fang Keon, Kristine A. Rubinstein, John L. Zeng, Si-Xin Zhang, Shuang Chen, Qiu-Ling Fu, Jing Li, Min Shen, Han-Ming Lu, Jin-Jian Chen, Xiu-Ping Lu, Jia-Hong Toosendanin, a novel potent vacuolar-type H(+)-translocating ATPase inhibitor, sensitizes cancer cells to chemotherapy by blocking protective autophagy |
title | Toosendanin, a novel potent vacuolar-type H(+)-translocating ATPase inhibitor, sensitizes cancer cells to chemotherapy by blocking protective autophagy |
title_full | Toosendanin, a novel potent vacuolar-type H(+)-translocating ATPase inhibitor, sensitizes cancer cells to chemotherapy by blocking protective autophagy |
title_fullStr | Toosendanin, a novel potent vacuolar-type H(+)-translocating ATPase inhibitor, sensitizes cancer cells to chemotherapy by blocking protective autophagy |
title_full_unstemmed | Toosendanin, a novel potent vacuolar-type H(+)-translocating ATPase inhibitor, sensitizes cancer cells to chemotherapy by blocking protective autophagy |
title_short | Toosendanin, a novel potent vacuolar-type H(+)-translocating ATPase inhibitor, sensitizes cancer cells to chemotherapy by blocking protective autophagy |
title_sort | toosendanin, a novel potent vacuolar-type h(+)-translocating atpase inhibitor, sensitizes cancer cells to chemotherapy by blocking protective autophagy |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9066121/ https://www.ncbi.nlm.nih.gov/pubmed/35541921 http://dx.doi.org/10.7150/ijbs.71041 |
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