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Capsaicin binds the N-terminus of Hsp90, induces lysosomal degradation of Hsp70, and enhances the anti-tumor effects of 17-AAG (Tanespimycin)

Heat shock protein 90 (Hsp90) and its co-chaperones promote cancer, and targeting Hsp90 holds promise for cancer treatment. Most of the efforts to harness this potential have focused on targeting the Hsp90 N-terminus ATP binding site. Although newer-generation inhibitors have shown improved efficacy...

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Autores principales: Patwardhan, Chaitanya A., Kommalapati, Vamsi Krishna, Llbiyi, Taoufik, Singh, Digvijay, Alfa, Eyad, Horuzsko, Anatolij, Korkaya, Hasan, Panda, Siva, Reilly, Christopher A., Popik, Vladimir, Chadli, Ahmed
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10447550/
https://www.ncbi.nlm.nih.gov/pubmed/37612326
http://dx.doi.org/10.1038/s41598-023-40933-9
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author Patwardhan, Chaitanya A.
Kommalapati, Vamsi Krishna
Llbiyi, Taoufik
Singh, Digvijay
Alfa, Eyad
Horuzsko, Anatolij
Korkaya, Hasan
Panda, Siva
Reilly, Christopher A.
Popik, Vladimir
Chadli, Ahmed
author_facet Patwardhan, Chaitanya A.
Kommalapati, Vamsi Krishna
Llbiyi, Taoufik
Singh, Digvijay
Alfa, Eyad
Horuzsko, Anatolij
Korkaya, Hasan
Panda, Siva
Reilly, Christopher A.
Popik, Vladimir
Chadli, Ahmed
author_sort Patwardhan, Chaitanya A.
collection PubMed
description Heat shock protein 90 (Hsp90) and its co-chaperones promote cancer, and targeting Hsp90 holds promise for cancer treatment. Most of the efforts to harness this potential have focused on targeting the Hsp90 N-terminus ATP binding site. Although newer-generation inhibitors have shown improved efficacy in aggressive cancers, induction of the cellular heat shock response (HSR) by these inhibitors is thought to limit their clinical efficacy. Therefore, Hsp90 inhibitors with novel mechanisms of action and that do not trigger the HSR would be advantageous. Here, we investigated the mechanism by which capsaicin inhibits Hsp90. Through mutagenesis, chemical modifications, and proteomic studies, we show that capsaicin binds to the N-terminus of Hsp90 and inhibits its ATPase activity. Consequently, capsaicin and its analogs inhibit Hsp90 ATPase-dependent progesterone receptor reconstitution in vitro. Capsaicin did not induce the HSR, instead, it promoted the degradation of Hsp70 through the lysosome-autophagy pathway. Remarkably, capsaicin did not induce degradation of the constitutively expressed cognate Hsc70, indicating selectivity for Hsp70. Combined treatments of capsaicin and the Hsp90 inhibitor 17-AAG improved the anti-tumor efficacy of 17-AAG in cell culture and tridimensional tumor spheroid growth assays using breast and prostate cancer models. Consistent with this, in silico docking studies revealed that capsaicin binding to the ATP binding site of Hsp90 was distinct from classical N-terminus Hsp90 inhibitors, indicating a novel mechanism of action. Collectively, these findings support the use of capsaicin as a chemical scaffold to develop novel Hsp90 N-terminus inhibitors as well as its ability to be a potential cancer co-therapeutic.
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spelling pubmed-104475502023-08-25 Capsaicin binds the N-terminus of Hsp90, induces lysosomal degradation of Hsp70, and enhances the anti-tumor effects of 17-AAG (Tanespimycin) Patwardhan, Chaitanya A. Kommalapati, Vamsi Krishna Llbiyi, Taoufik Singh, Digvijay Alfa, Eyad Horuzsko, Anatolij Korkaya, Hasan Panda, Siva Reilly, Christopher A. Popik, Vladimir Chadli, Ahmed Sci Rep Article Heat shock protein 90 (Hsp90) and its co-chaperones promote cancer, and targeting Hsp90 holds promise for cancer treatment. Most of the efforts to harness this potential have focused on targeting the Hsp90 N-terminus ATP binding site. Although newer-generation inhibitors have shown improved efficacy in aggressive cancers, induction of the cellular heat shock response (HSR) by these inhibitors is thought to limit their clinical efficacy. Therefore, Hsp90 inhibitors with novel mechanisms of action and that do not trigger the HSR would be advantageous. Here, we investigated the mechanism by which capsaicin inhibits Hsp90. Through mutagenesis, chemical modifications, and proteomic studies, we show that capsaicin binds to the N-terminus of Hsp90 and inhibits its ATPase activity. Consequently, capsaicin and its analogs inhibit Hsp90 ATPase-dependent progesterone receptor reconstitution in vitro. Capsaicin did not induce the HSR, instead, it promoted the degradation of Hsp70 through the lysosome-autophagy pathway. Remarkably, capsaicin did not induce degradation of the constitutively expressed cognate Hsc70, indicating selectivity for Hsp70. Combined treatments of capsaicin and the Hsp90 inhibitor 17-AAG improved the anti-tumor efficacy of 17-AAG in cell culture and tridimensional tumor spheroid growth assays using breast and prostate cancer models. Consistent with this, in silico docking studies revealed that capsaicin binding to the ATP binding site of Hsp90 was distinct from classical N-terminus Hsp90 inhibitors, indicating a novel mechanism of action. Collectively, these findings support the use of capsaicin as a chemical scaffold to develop novel Hsp90 N-terminus inhibitors as well as its ability to be a potential cancer co-therapeutic. Nature Publishing Group UK 2023-08-23 /pmc/articles/PMC10447550/ /pubmed/37612326 http://dx.doi.org/10.1038/s41598-023-40933-9 Text en © The Author(s) 2023 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Patwardhan, Chaitanya A.
Kommalapati, Vamsi Krishna
Llbiyi, Taoufik
Singh, Digvijay
Alfa, Eyad
Horuzsko, Anatolij
Korkaya, Hasan
Panda, Siva
Reilly, Christopher A.
Popik, Vladimir
Chadli, Ahmed
Capsaicin binds the N-terminus of Hsp90, induces lysosomal degradation of Hsp70, and enhances the anti-tumor effects of 17-AAG (Tanespimycin)
title Capsaicin binds the N-terminus of Hsp90, induces lysosomal degradation of Hsp70, and enhances the anti-tumor effects of 17-AAG (Tanespimycin)
title_full Capsaicin binds the N-terminus of Hsp90, induces lysosomal degradation of Hsp70, and enhances the anti-tumor effects of 17-AAG (Tanespimycin)
title_fullStr Capsaicin binds the N-terminus of Hsp90, induces lysosomal degradation of Hsp70, and enhances the anti-tumor effects of 17-AAG (Tanespimycin)
title_full_unstemmed Capsaicin binds the N-terminus of Hsp90, induces lysosomal degradation of Hsp70, and enhances the anti-tumor effects of 17-AAG (Tanespimycin)
title_short Capsaicin binds the N-terminus of Hsp90, induces lysosomal degradation of Hsp70, and enhances the anti-tumor effects of 17-AAG (Tanespimycin)
title_sort capsaicin binds the n-terminus of hsp90, induces lysosomal degradation of hsp70, and enhances the anti-tumor effects of 17-aag (tanespimycin)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10447550/
https://www.ncbi.nlm.nih.gov/pubmed/37612326
http://dx.doi.org/10.1038/s41598-023-40933-9
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