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Targeting lysosomal cysteine protease cathepsin S reveals immunomodulatory therapeutic strategy for oxaliplatin-induced peripheral neuropathy
Rationale: Oxaliplatin-induced peripheral neuropathy (OIPN) is a common adverse effect that causes delayed treatment and poor prognosis among colorectal cancer (CRC) patients. However, its mechanism remains elusive, and no effective treatment is available. Methods: We employed a prospective cohort s...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978314/ https://www.ncbi.nlm.nih.gov/pubmed/33754020 http://dx.doi.org/10.7150/thno.54793 |
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author | Chen, Szu-Jung Chen, Li-Hsien Yeh, Yu-Min Lin, Chou-Ching K Lin, Peng-Chan Huang, Han-Wei Shen, Meng-Ru Lin, Bo-Wen Lee, Jeng-Chang Lee, Cheng-Che Lee, Yueh-Feng Chiang, Huai-Chueh Chang, Jang-Yang |
author_facet | Chen, Szu-Jung Chen, Li-Hsien Yeh, Yu-Min Lin, Chou-Ching K Lin, Peng-Chan Huang, Han-Wei Shen, Meng-Ru Lin, Bo-Wen Lee, Jeng-Chang Lee, Cheng-Che Lee, Yueh-Feng Chiang, Huai-Chueh Chang, Jang-Yang |
author_sort | Chen, Szu-Jung |
collection | PubMed |
description | Rationale: Oxaliplatin-induced peripheral neuropathy (OIPN) is a common adverse effect that causes delayed treatment and poor prognosis among colorectal cancer (CRC) patients. However, its mechanism remains elusive, and no effective treatment is available. Methods: We employed a prospective cohort study of adult patients with pathologically confirmed stage III CRC receiving adjuvant chemotherapy with an oxaliplatin-based regimen for investigating OIPN. To further validate the clinical manifestations and identify a potential therapeutic strategy, animal models, and in vitro studies on the mechanism of OIPN were applied. Results: Our work found that (1) consistent with clinical findings, OIPN was observed in animal models. Targeting the enzymatic activity of cathepsin S (CTSS) by pharmacological blockade and gene deficiency strategy alleviates the manifestations of OIPN. (2) Oxaliplatin treatment increases CTSS expression by enhancing cytosol translocation of interferon response factor 1 (IRF1), which then facilitates STIM-dependent store-operated Ca(2+) entry homeostasis. (3) The cytokine array demonstrated an increase in anti-inflammatory cytokines and suppression of proinflammatory cytokines in mice treated with RJW-58. (4) Mechanistically, inhibiting CTSS facilitated olfactory receptors transcription factor 1 release from P300/CBP binding, which enhanced binding to the interleukin-10 (IL-10) promoter region, driving IL-10 downstream signaling pathway. (5) Serum CTSS expression is increased in CRC patients with oxaliplatin-induced neurotoxicity. Conclusions: We highlighted the critical role of CTSS in OIPN, which provides a therapeutic strategy for the common adverse side effects of oxaliplatin. |
format | Online Article Text |
id | pubmed-7978314 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-79783142021-03-21 Targeting lysosomal cysteine protease cathepsin S reveals immunomodulatory therapeutic strategy for oxaliplatin-induced peripheral neuropathy Chen, Szu-Jung Chen, Li-Hsien Yeh, Yu-Min Lin, Chou-Ching K Lin, Peng-Chan Huang, Han-Wei Shen, Meng-Ru Lin, Bo-Wen Lee, Jeng-Chang Lee, Cheng-Che Lee, Yueh-Feng Chiang, Huai-Chueh Chang, Jang-Yang Theranostics Research Paper Rationale: Oxaliplatin-induced peripheral neuropathy (OIPN) is a common adverse effect that causes delayed treatment and poor prognosis among colorectal cancer (CRC) patients. However, its mechanism remains elusive, and no effective treatment is available. Methods: We employed a prospective cohort study of adult patients with pathologically confirmed stage III CRC receiving adjuvant chemotherapy with an oxaliplatin-based regimen for investigating OIPN. To further validate the clinical manifestations and identify a potential therapeutic strategy, animal models, and in vitro studies on the mechanism of OIPN were applied. Results: Our work found that (1) consistent with clinical findings, OIPN was observed in animal models. Targeting the enzymatic activity of cathepsin S (CTSS) by pharmacological blockade and gene deficiency strategy alleviates the manifestations of OIPN. (2) Oxaliplatin treatment increases CTSS expression by enhancing cytosol translocation of interferon response factor 1 (IRF1), which then facilitates STIM-dependent store-operated Ca(2+) entry homeostasis. (3) The cytokine array demonstrated an increase in anti-inflammatory cytokines and suppression of proinflammatory cytokines in mice treated with RJW-58. (4) Mechanistically, inhibiting CTSS facilitated olfactory receptors transcription factor 1 release from P300/CBP binding, which enhanced binding to the interleukin-10 (IL-10) promoter region, driving IL-10 downstream signaling pathway. (5) Serum CTSS expression is increased in CRC patients with oxaliplatin-induced neurotoxicity. Conclusions: We highlighted the critical role of CTSS in OIPN, which provides a therapeutic strategy for the common adverse side effects of oxaliplatin. Ivyspring International Publisher 2021-03-04 /pmc/articles/PMC7978314/ /pubmed/33754020 http://dx.doi.org/10.7150/thno.54793 Text en © The author(s) 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 Chen, Szu-Jung Chen, Li-Hsien Yeh, Yu-Min Lin, Chou-Ching K Lin, Peng-Chan Huang, Han-Wei Shen, Meng-Ru Lin, Bo-Wen Lee, Jeng-Chang Lee, Cheng-Che Lee, Yueh-Feng Chiang, Huai-Chueh Chang, Jang-Yang Targeting lysosomal cysteine protease cathepsin S reveals immunomodulatory therapeutic strategy for oxaliplatin-induced peripheral neuropathy |
title | Targeting lysosomal cysteine protease cathepsin S reveals immunomodulatory therapeutic strategy for oxaliplatin-induced peripheral neuropathy |
title_full | Targeting lysosomal cysteine protease cathepsin S reveals immunomodulatory therapeutic strategy for oxaliplatin-induced peripheral neuropathy |
title_fullStr | Targeting lysosomal cysteine protease cathepsin S reveals immunomodulatory therapeutic strategy for oxaliplatin-induced peripheral neuropathy |
title_full_unstemmed | Targeting lysosomal cysteine protease cathepsin S reveals immunomodulatory therapeutic strategy for oxaliplatin-induced peripheral neuropathy |
title_short | Targeting lysosomal cysteine protease cathepsin S reveals immunomodulatory therapeutic strategy for oxaliplatin-induced peripheral neuropathy |
title_sort | targeting lysosomal cysteine protease cathepsin s reveals immunomodulatory therapeutic strategy for oxaliplatin-induced peripheral neuropathy |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978314/ https://www.ncbi.nlm.nih.gov/pubmed/33754020 http://dx.doi.org/10.7150/thno.54793 |
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