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
School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China.
School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University - Shenzhen Campus, Shenzhen, Guangdong, China.
J Immunother Cancer. 2022 Nov;10(11). doi: 10.1136/jitc-2022-005503.
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.
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.
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=65 nM) and effectively inhibit its deaminase activity (IC=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.
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.
癌症的发生在很大程度上依赖于体细胞突变的积累，这表明开发针对突变驱动因素的癌症化学预防剂具有潜力。然而，尚未确定能够有效抑制突变驱动因素的理想癌症化学预防剂。
对泛癌患者进行了载脂蛋白B mRNA编辑酶催化多肽样3B（APOBEC3B）的体细胞突变特征和表达分析。进行计算机辅助筛选和基于骨架的搜索，以鉴定可抑制APOBEC3B活性的天然产物。利用4-硝基喹啉-1-氧化物（4-NQO）诱导的自发性食管鳞状细胞癌（ESCC）和氧化偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）诱导的自发性结肠癌小鼠模型，研究APOBEC3B抑制剂对预防体细胞突变积累和癌症进展的影响。
在此，我们发现胞苷脱氨酶APOBEC3B相关的体细胞突变在多种癌症中广泛存在，其过表达表明生存率较低。SMC247（3,5-二碘酪氨酸）作为一种无副作用的海带碘来源，能与APOBEC3B紧密结合（K = 65 nM）并有效抑制其脱氨酶活性（IC = 1.69 μM）。有趣的是，3,5-二碘酪氨酸可显著减少突变簇，阻止癌前病变进展，并延长4-NQO诱导的自发性ESCC和AOM/DSS诱导的自发性结肠癌小鼠模型的生存期。此外，3,5-二碘酪氨酸可减轻结肠炎，通过肿瘤微环境中的白细胞介素-15增加T淋巴细胞的比例和功能。当3,5-二碘酪氨酸与程序性死亡受体1/程序性死亡配体1（PD-1/PD-L1）阻断剂联合使用时，观察到协同的癌症预防效果。
这是第一项概念验证研究，阐明天然产物3,5-二碘酪氨酸可通过抑制APOBEC3B的酶活性来预防体细胞突变积累和癌症进展。此外，3,5-二碘酪氨酸可减轻结肠炎，并通过肿瘤微环境中的白细胞介素-15增加T淋巴细胞的浸润和功能。3,5-二碘酪氨酸与PD-1/PD-L1阻断剂联合使用可产生协同的癌症预防效果，这表明了一种预防体细胞突变积累和免疫抑制微环境恶化的新策略。
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