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Identification of natural product 3, 5-diiodotyrosine as APOBEC3B inhibitor to prevent somatic mutation accumulation and cancer progression

BACKGROUND: The development of cancer is largely dependent on the accumulation of somatic mutations, indicating the potential to develop cancer chemoprevention agents targeting mutation drivers. However, ideal cancer chemoprevention agents that can effectively inhibit the mutation drivers have not b...

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Autores principales: Chen, Chunxia, Sui, Xinghua, Ning, Haoming, Sun, Yixuan, Du, Jiangfeng, Chen, Xiaotong, Zhou, Xiuman, Chen, Guanyu, Shen, Wenhui, Pang, Liwei, Zhou, Xiaowen, Shi, Ranran, Li, Wanqiong, Wang, Hongfei, Zhao, Wenshan, Zhai, Wenjie, Qi, Yuanming, Wu, Yahong, Gao, Yanfeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9639148/
https://www.ncbi.nlm.nih.gov/pubmed/36323433
http://dx.doi.org/10.1136/jitc-2022-005503
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author Chen, Chunxia
Sui, Xinghua
Ning, Haoming
Sun, Yixuan
Du, Jiangfeng
Chen, Xiaotong
Zhou, Xiuman
Chen, Guanyu
Shen, Wenhui
Pang, Liwei
Zhou, Xiaowen
Shi, Ranran
Li, Wanqiong
Wang, Hongfei
Zhao, Wenshan
Zhai, Wenjie
Qi, Yuanming
Wu, Yahong
Gao, Yanfeng
author_facet Chen, Chunxia
Sui, Xinghua
Ning, Haoming
Sun, Yixuan
Du, Jiangfeng
Chen, Xiaotong
Zhou, Xiuman
Chen, Guanyu
Shen, Wenhui
Pang, Liwei
Zhou, Xiaowen
Shi, Ranran
Li, Wanqiong
Wang, Hongfei
Zhao, Wenshan
Zhai, Wenjie
Qi, Yuanming
Wu, Yahong
Gao, Yanfeng
author_sort Chen, Chunxia
collection PubMed
description BACKGROUND: The development of cancer is largely dependent on the accumulation of somatic mutations, indicating the potential to develop cancer chemoprevention agents targeting mutation drivers. However, ideal cancer chemoprevention agents that can effectively inhibit the mutation drivers have not been identified yet. METHODS: The somatic mutation signatures and expression analyses of APOBEC3B were performed in patient with pan-cancer. The computer-aided screening and skeleton-based searching were performed to identify natural products that can inhibit the activity of APOBEC3B. 4-nitroquinoline-1-oxide (4-NQO)-induced spontaneous esophageal squamous cell carcinoma (ESCC) and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced spontaneous colon cancer mouse models were conducted to investigate the influences of APOBEC3B inhibitor on the prevention of somatic mutation accumulation and cancer progression. RESULTS: Here, we discovered that the cytidine deaminase APOBEC3B correlated somatic mutations were widely observed in a variety of cancers, and its overexpression indicated poor survival. SMC247 (3, 5-diiodotyrosine), as a source of kelp iodine without side effects, could strongly bind APOBEC3B (K(D)=65 nM) and effectively inhibit its deaminase activity (IC(50)=1.69 µM). Interestingly, 3, 5-diiodotyrosine could significantly reduce the clusters of mutations, prevent the precancerous lesion progression, and prolong the survival in 4-NQO-induced spontaneous ESCC and AOM/DSS-induced spontaneous colon cancer mouse models. Furthermore, 3, 5-diiodotyrosine could reduce colitis, increase the proportion and function of T lymphocytes via IL-15 in tumor microenvironment. The synergistic cancer prevention effects were observed when 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade. CONCLUSIONS: This is the first prove-of-concept study to elucidate that the natural product 3, 5-diiodotyrosine could prevent somatic mutation accumulation and cancer progression through inhibiting the enzymatic activity of APOBEC3B. In addition, 3, 5-diiodotyrosine could reduce the colitis and increase the infiltration and function of T lymphocytes via IL-15 in tumor microenvironment. 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade could elicit synergistic cancer prevention effects, indicating a novel strategy for both prevent the somatic mutation accumulation and the immune-suppressive microenvironment exacerbation.
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spelling pubmed-96391482022-11-08 Identification of natural product 3, 5-diiodotyrosine as APOBEC3B inhibitor to prevent somatic mutation accumulation and cancer progression Chen, Chunxia Sui, Xinghua Ning, Haoming Sun, Yixuan Du, Jiangfeng Chen, Xiaotong Zhou, Xiuman Chen, Guanyu Shen, Wenhui Pang, Liwei Zhou, Xiaowen Shi, Ranran Li, Wanqiong Wang, Hongfei Zhao, Wenshan Zhai, Wenjie Qi, Yuanming Wu, Yahong Gao, Yanfeng J Immunother Cancer Basic Tumor Immunology BACKGROUND: The development of cancer is largely dependent on the accumulation of somatic mutations, indicating the potential to develop cancer chemoprevention agents targeting mutation drivers. However, ideal cancer chemoprevention agents that can effectively inhibit the mutation drivers have not been identified yet. METHODS: The somatic mutation signatures and expression analyses of APOBEC3B were performed in patient with pan-cancer. The computer-aided screening and skeleton-based searching were performed to identify natural products that can inhibit the activity of APOBEC3B. 4-nitroquinoline-1-oxide (4-NQO)-induced spontaneous esophageal squamous cell carcinoma (ESCC) and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced spontaneous colon cancer mouse models were conducted to investigate the influences of APOBEC3B inhibitor on the prevention of somatic mutation accumulation and cancer progression. RESULTS: Here, we discovered that the cytidine deaminase APOBEC3B correlated somatic mutations were widely observed in a variety of cancers, and its overexpression indicated poor survival. SMC247 (3, 5-diiodotyrosine), as a source of kelp iodine without side effects, could strongly bind APOBEC3B (K(D)=65 nM) and effectively inhibit its deaminase activity (IC(50)=1.69 µM). Interestingly, 3, 5-diiodotyrosine could significantly reduce the clusters of mutations, prevent the precancerous lesion progression, and prolong the survival in 4-NQO-induced spontaneous ESCC and AOM/DSS-induced spontaneous colon cancer mouse models. Furthermore, 3, 5-diiodotyrosine could reduce colitis, increase the proportion and function of T lymphocytes via IL-15 in tumor microenvironment. The synergistic cancer prevention effects were observed when 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade. CONCLUSIONS: This is the first prove-of-concept study to elucidate that the natural product 3, 5-diiodotyrosine could prevent somatic mutation accumulation and cancer progression through inhibiting the enzymatic activity of APOBEC3B. In addition, 3, 5-diiodotyrosine could reduce the colitis and increase the infiltration and function of T lymphocytes via IL-15 in tumor microenvironment. 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade could elicit synergistic cancer prevention effects, indicating a novel strategy for both prevent the somatic mutation accumulation and the immune-suppressive microenvironment exacerbation. BMJ Publishing Group 2022-11-02 /pmc/articles/PMC9639148/ /pubmed/36323433 http://dx.doi.org/10.1136/jitc-2022-005503 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Basic Tumor Immunology
Chen, Chunxia
Sui, Xinghua
Ning, Haoming
Sun, Yixuan
Du, Jiangfeng
Chen, Xiaotong
Zhou, Xiuman
Chen, Guanyu
Shen, Wenhui
Pang, Liwei
Zhou, Xiaowen
Shi, Ranran
Li, Wanqiong
Wang, Hongfei
Zhao, Wenshan
Zhai, Wenjie
Qi, Yuanming
Wu, Yahong
Gao, Yanfeng
Identification of natural product 3, 5-diiodotyrosine as APOBEC3B inhibitor to prevent somatic mutation accumulation and cancer progression
title Identification of natural product 3, 5-diiodotyrosine as APOBEC3B inhibitor to prevent somatic mutation accumulation and cancer progression
title_full Identification of natural product 3, 5-diiodotyrosine as APOBEC3B inhibitor to prevent somatic mutation accumulation and cancer progression
title_fullStr Identification of natural product 3, 5-diiodotyrosine as APOBEC3B inhibitor to prevent somatic mutation accumulation and cancer progression
title_full_unstemmed Identification of natural product 3, 5-diiodotyrosine as APOBEC3B inhibitor to prevent somatic mutation accumulation and cancer progression
title_short Identification of natural product 3, 5-diiodotyrosine as APOBEC3B inhibitor to prevent somatic mutation accumulation and cancer progression
title_sort identification of natural product 3, 5-diiodotyrosine as apobec3b inhibitor to prevent somatic mutation accumulation and cancer progression
topic Basic Tumor Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9639148/
https://www.ncbi.nlm.nih.gov/pubmed/36323433
http://dx.doi.org/10.1136/jitc-2022-005503
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