Targeting FROUNT with disulfiram suppresses macrophage accumulation and its tumor-promoting properties
| العنوان: | Targeting FROUNT with disulfiram suppresses macrophage accumulation and its tumor-promoting properties |
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| المؤلفون: | Sana Yokoi, Takayoshi Okabe, Ichio Shimada, Toshihiko Iizasa, Etsuko Toda, Koji Ohnishi, Francis H. W. Shand, Shiro Kanegasaki, Hiroki Nagase, Meiji Itakura, Hirofumi Nakano, Mitsuhiro Takeda, Sosuke Yoshinaga, Miki Ohira, Ming-Rong Zhang, Kazuhiro Okumura, Yuya Terashima, Hirotatsu Kojima, Kana Kokubo, Ming Chen Chen, Mikiya Otsuji, Yoshihiro Komohara, Yutaka Kofuku, Hirofumi Rokutan, Hiroaki Terasawa, Kouji Matsushima, Akira Shimizu |
| المصدر: | Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020) |
| بيانات النشر: | Springer Science and Business Media LLC, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Chemokine, Lung Neoplasms, medicine.medical_treatment, General Physics and Astronomy, Cancer immunotherapy, Monocytes, Chemokine receptor, 0302 clinical medicine, Risk Factors, Disulfiram, Macrophage, Neoplasm Metastasis, lcsh:Science, Gene knockdown, Multidisciplinary, biology, Chemistry, Chemotaxis, High-throughput screening, Drug Synergism, Prognosis, Gene Expression Regulation, Neoplastic, Clathrin Heavy Chains, 030220 oncology & carcinogenesis, Disease Progression, Tumour immunology, Immunotherapy, Chemokines, Cancer microenvironment, Science, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Animals, Cell Proliferation, Macrophages, General Chemistry, Immune checkpoint, Mice, Inbred C57BL, Nuclear Pore Complex Proteins, Kinetics, 030104 developmental biology, Tumor progression, biology.protein, Cancer research, lcsh:Q |
| الوصف: | Tumor-associated macrophages affect tumor progression and resistance to immune checkpoint therapy. Here, we identify the chemokine signal regulator FROUNT as a target to control tumor-associated macrophages. The low level FROUNT expression in patients with cancer correlates with better clinical outcomes. Frount-deficiency markedly reduces tumor progression and decreases macrophage tumor-promoting activity. FROUNT is highly expressed in macrophages, and its myeloid-specific deletion impairs tumor growth. Further, the anti-alcoholism drug disulfiram (DSF) acts as a potent inhibitor of FROUNT. DSF interferes with FROUNT-chemokine receptor interactions via direct binding to a specific site of the chemokine receptor-binding domain of FROUNT, leading to inhibition of macrophage responses. DSF monotherapy reduces tumor progression and decreases macrophage tumor-promoting activity, as seen in the case of Frount-deficiency. Moreover, co-treatment with DSF and an immune checkpoint antibody synergistically inhibits tumor growth. Thus, inhibition of FROUNT by DSF represents a promising strategy for macrophage-targeted cancer therapy. The cytoplasmic protein FROUNT can bind to chemokine receptors and enhance chemokine signalling. Here, the authors show that inhibiting FROUNT in macrophages either by knockdown of the gene or using the anti-alcoholism drug disulfiram, results in a reduction in tumour growth. |
| تدمد: | 2041-1723 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::be5ea522550499798f4ebb8e0eda0242 https://doi.org/10.1038/s41467-020-14338-5 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....be5ea522550499798f4ebb8e0eda0242 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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