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A marine-derived small molecule induces immunogenic cell death against triple-negative breast cancer through ER stress-CHOP pathway
Although triple-negative breast cancer (TNBC) is the most refractory subtype among all breast cancers, it has been shown to have higher immune infiltration than other subtypes. We identified the marine-derived small molecule MHO7, which acts as a potent immunogenic cell death (ICD) inducer through t...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Ivyspring International Publisher
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9066120/ https://www.ncbi.nlm.nih.gov/pubmed/35541893 http://dx.doi.org/10.7150/ijbs.70975 |
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author | Wen, Haiyan Zhong, Yinxian Yin, Yuping Qin, Kongming Yang, Liang Li, Dan Yu, Wulin Yang, Chenjie Deng, Zixin Hong, Kui |
author_facet | Wen, Haiyan Zhong, Yinxian Yin, Yuping Qin, Kongming Yang, Liang Li, Dan Yu, Wulin Yang, Chenjie Deng, Zixin Hong, Kui |
author_sort | Wen, Haiyan |
collection | PubMed |
description | Although triple-negative breast cancer (TNBC) is the most refractory subtype among all breast cancers, it has been shown to have higher immune infiltration than other subtypes. We identified the marine-derived small molecule MHO7, which acts as a potent immunogenic cell death (ICD) inducer through the endoplasmic reticulum (ER) stress-C/EBP-homologous protein (CHOP) pathway, to treat TNBC. MHO7 exerted cytostatic and cytotoxic effects on TNBC cells at an IC(50) of 0.96-1.75 µM and suppressed tumor growth with an approximately 80% inhibition rate at a dose of 60 mg/kg. In 4T1 cell tumor-bearing mice, 30 mg/kg MHO7 inhibited pulmonary metastasis with an efficacy of 70.26%. Transcriptome analyses revealed that MHO7 changed the transcription of genes related to ribosome and protein processes in the ER. MHO7 also triggered reactive oxygen species (ROS) generation and attenuated glutathione (GSH) levels, which caused excessive oxidative stress and ER stress via the PERK/eIF2α/AFT4/CHOP pathway and led to cell apoptosis. ER stress and ROS production facilitated the release of ICD-related danger-associated molecular patterns (DAMPs) from TNBC cells, which activated the immune response in vivo, as indicated by the release of antitumor cytokines such as IL-6, IL-1β, IFN-γ, and TNF-α, increases in CD86(+) and MHC-II dendritic cells and CD4(+) and CD8(+) T cells and a decrease in regulatory T cells (Tregs). These results reveal that MHO7 triggers an aggressive stress response to amplify tumor immunogenicity and induce a robust immune response. This synergistic effect inhibits primary breast cancer growth and spontaneous metastasis in TNBC, providing a new strategy for TNBC treatment. |
format | Online Article Text |
id | pubmed-9066120 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-90661202022-05-09 A marine-derived small molecule induces immunogenic cell death against triple-negative breast cancer through ER stress-CHOP pathway Wen, Haiyan Zhong, Yinxian Yin, Yuping Qin, Kongming Yang, Liang Li, Dan Yu, Wulin Yang, Chenjie Deng, Zixin Hong, Kui Int J Biol Sci Research Paper Although triple-negative breast cancer (TNBC) is the most refractory subtype among all breast cancers, it has been shown to have higher immune infiltration than other subtypes. We identified the marine-derived small molecule MHO7, which acts as a potent immunogenic cell death (ICD) inducer through the endoplasmic reticulum (ER) stress-C/EBP-homologous protein (CHOP) pathway, to treat TNBC. MHO7 exerted cytostatic and cytotoxic effects on TNBC cells at an IC(50) of 0.96-1.75 µM and suppressed tumor growth with an approximately 80% inhibition rate at a dose of 60 mg/kg. In 4T1 cell tumor-bearing mice, 30 mg/kg MHO7 inhibited pulmonary metastasis with an efficacy of 70.26%. Transcriptome analyses revealed that MHO7 changed the transcription of genes related to ribosome and protein processes in the ER. MHO7 also triggered reactive oxygen species (ROS) generation and attenuated glutathione (GSH) levels, which caused excessive oxidative stress and ER stress via the PERK/eIF2α/AFT4/CHOP pathway and led to cell apoptosis. ER stress and ROS production facilitated the release of ICD-related danger-associated molecular patterns (DAMPs) from TNBC cells, which activated the immune response in vivo, as indicated by the release of antitumor cytokines such as IL-6, IL-1β, IFN-γ, and TNF-α, increases in CD86(+) and MHC-II dendritic cells and CD4(+) and CD8(+) T cells and a decrease in regulatory T cells (Tregs). These results reveal that MHO7 triggers an aggressive stress response to amplify tumor immunogenicity and induce a robust immune response. This synergistic effect inhibits primary breast cancer growth and spontaneous metastasis in TNBC, providing a new strategy for TNBC treatment. Ivyspring International Publisher 2022-04-11 /pmc/articles/PMC9066120/ /pubmed/35541893 http://dx.doi.org/10.7150/ijbs.70975 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 Wen, Haiyan Zhong, Yinxian Yin, Yuping Qin, Kongming Yang, Liang Li, Dan Yu, Wulin Yang, Chenjie Deng, Zixin Hong, Kui A marine-derived small molecule induces immunogenic cell death against triple-negative breast cancer through ER stress-CHOP pathway |
title | A marine-derived small molecule induces immunogenic cell death against triple-negative breast cancer through ER stress-CHOP pathway |
title_full | A marine-derived small molecule induces immunogenic cell death against triple-negative breast cancer through ER stress-CHOP pathway |
title_fullStr | A marine-derived small molecule induces immunogenic cell death against triple-negative breast cancer through ER stress-CHOP pathway |
title_full_unstemmed | A marine-derived small molecule induces immunogenic cell death against triple-negative breast cancer through ER stress-CHOP pathway |
title_short | A marine-derived small molecule induces immunogenic cell death against triple-negative breast cancer through ER stress-CHOP pathway |
title_sort | marine-derived small molecule induces immunogenic cell death against triple-negative breast cancer through er stress-chop pathway |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9066120/ https://www.ncbi.nlm.nih.gov/pubmed/35541893 http://dx.doi.org/10.7150/ijbs.70975 |
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