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IGF2BP1的变构调节作为激活肿瘤免疫微环境的新策略。

Allosteric Regulation of IGF2BP1 as a Novel Strategy for the Activation of Tumor Immune Microenvironment.

作者信息

Liu Yang, Guo Qiang, Yang Heng, Zhang Xiao-Wen, Feng Na, Wang Jing-Kang, Liu Ting-Ting, Zeng Ke-Wu, Tu Peng-Fei

机构信息

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.

Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, 49 N. Garden Road, Haidian District, Beijing 100191, China.

出版信息

ACS Cent Sci. 2022 Aug 24;8(8):1102-1115. doi: 10.1021/acscentsci.2c00107. Epub 2022 May 17.

DOI:10.1021/acscentsci.2c00107
PMID:36032766
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9413439/
Abstract

Tumor immune microenvironment (TIME) regulators are promising cancer immunotherapeutic targets. IGF2BP1, as a crucial -methyladenosine (mA) reader protein, recognizes mA target transcripts, ultimately leading to cancer development. However, currently, the biological function of IGF2BP1 in regulating the TIME is not well-understood. In this study, we report that IGF2BP1 knockdown induces cancer cell apoptosis, thereby significantly not only activating immune cell infiltration including CD4, CD8 T cells, CD56 NK cells, and F4/80 macrophage but also decreasing PD-L1 expression in hepatocellular carcinoma (HCC). Then, chemical genetics identifies a small-molecule cucurbitacin B (CuB), which directly targets IGF2BP1 at a unique site (Cys253) in the KH1-2 domains. This leads to a pharmacological allosteric effect to block IGF2BP1 recognition of mA mRNA targets such as , which is highly associated with cell apoptosis and immune response. In vivo, CuB exhibits an obvious anti-HCC effect through inducing apoptosis and subsequently recruits immune cells to tumor microenvironment as well as blocking PD-L1 expression. Collectively, IGF2BP1 may serve as a novel pharmacological allosteric target for anticancer therapeutics via mediating TIME.

摘要

肿瘤免疫微环境（TIME）调节因子是很有前景的癌症免疫治疗靶点。IGF2BP1作为一种关键的N6-甲基腺苷（m6A）识别蛋白，识别m6A靶转录本，最终导致癌症发展。然而，目前IGF2BP1在调节TIME中的生物学功能尚不清楚。在本研究中，我们报道IGF2BP1敲低诱导癌细胞凋亡，从而不仅显著激活包括CD4、CD8 T细胞、CD56 NK细胞和F4/80巨噬细胞在内的免疫细胞浸润，还降低肝细胞癌（HCC）中PD-L1的表达。然后，化学遗传学鉴定出一种小分子葫芦素B（CuB），它在KH1-2结构域的一个独特位点（Cys253）直接靶向IGF2BP1。这导致一种药理学变构效应，以阻断IGF2BP1对m6A mRNA靶标的识别，如与细胞凋亡和免疫反应高度相关的靶标。在体内，CuB通过诱导凋亡表现出明显的抗HCC作用，随后将免疫细胞募集到肿瘤微环境中并阻断PD-L1表达。总的来说，IGF2BP1可能通过介导TIME作为抗癌治疗的新型药理学变构靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc7/9413439/aa717f07b548/oc2c00107_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc7/9413439/86f8a4d5fd74/oc2c00107_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc7/9413439/a995073f79fc/oc2c00107_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc7/9413439/f4bda6d06ff3/oc2c00107_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc7/9413439/058233fbb137/oc2c00107_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc7/9413439/d9ad6b07db70/oc2c00107_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc7/9413439/88a23fbb4727/oc2c00107_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc7/9413439/aa717f07b548/oc2c00107_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc7/9413439/86f8a4d5fd74/oc2c00107_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc7/9413439/a995073f79fc/oc2c00107_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc7/9413439/f4bda6d06ff3/oc2c00107_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc7/9413439/058233fbb137/oc2c00107_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc7/9413439/d9ad6b07db70/oc2c00107_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc7/9413439/88a23fbb4727/oc2c00107_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc7/9413439/aa717f07b548/oc2c00107_0007.jpg

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