气候变化领域集成服务门户(CCPortal): Therapeutic inhibition of USP9x-mediated Notch signaling in triple-negative breast cancer

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DOI	10.1073/pnas.2101592118
	Therapeutic inhibition of USP9x-mediated Notch signaling in triple-negative breast cancer
	Jaiswal A.; Murakami K.; Elia A.; Shibahara Y.; Done S.J.; Wood S.A.; Donato N.J.; Ohashi P.S.; Reedijk M.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:38
英文摘要	Triple-negative breast cancer (TNBC) is a breast cancer subtype that lacks targeted treatment options. The activation of the Notch developmental signaling pathway, which is a feature of TNBC, results in the secretion of proinflammatory cytokines and the recruitment of protumoral macrophages to the tumor microenvironment. While the Notch pathway is an obvious therapeutic target, its activity is ubiquitous, and predictably, anti-Notch therapies are burdened with significant on-target side effects. Previously, we discovered that, under conditions of cellular stress commonly found in the tumor microenvironment, the deubiquitinase USP9x forms a multiprotein complex with the pseudokinase tribbles homolog 3 (TRB3) that together activate the Notch pathway. Herein, we provide preclinical studies that support the potential of therapeutic USP9x inhibition to deactivate Notch. Using a murine TNBC model, we show that USP9x knockdown abrogates Notch activation, reducing the production of the proinflammatory cytokines, C-C motif chemokine ligand 2 (CCL2) and interleukin-1 beta (IL-1β). Concomitant with these molecular changes, a reduction in tumor inflammation, the augmentation of antitumor immune response, and the suppression of tumor growth were observed. The pharmacological inhibition of USP9x using G9, a partially selective, small-molecule USP9x inhibitor, reduced Notch activity, remodeled the tumor immune landscape, and reduced tumor growth without associated toxicity. Proving the role of Notch, the ectopic expression of the activated Notch1 intracellular domain rescued G9-induced effects. This work supports the potential of USP9x inhibition to target Notch in metabolically vulnerable tissues like TNBC, while sparing normal Notch-dependent tissues. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Breast cancer; Cytokine; Notch; TAMs; USP9x
语种	英语
scopus关键词	deubiquitinase; interleukin 1beta; monocyte chemotactic protein 1; Notch1 receptor; proteinase inhibitor; unclassified drug; USP9x deubiquitinase; cytokine; interleukin 1beta; Notch receptor; ubiquitin thiolesterase; USP9X protein, human; animal experiment; animal model; animal tissue; antineoplastic activity; Article; cancer inhibition; cancer tissue; controlled study; disease association; enzyme inhibition; female; human; human cell; immune response; mastitis; mouse; murine model; nonhuman; Notch signaling; preclinical study; protein degradation; protein domain; protein expression; protein function; toxicity testing; triple negative breast cancer; tumor growth; animal; cell proliferation; gene expression regulation; genetics; HEK293 cell line; macrophage; pathology; signal transduction; triple negative breast cancer; tumor cell line; tumor microenvironment; Animals; Cell Line, Tumor; Cell Proliferation; Cytokines; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Interleukin-1beta; Macrophages; Mice; Receptors, Notch; Signal Transduction; Triple Negative Breast Neoplasms; Tumor Microenvironment; Ubiquitin Thiolesterase
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251016
作者单位	Department of Medical Biophysics, University of Toronto, Toronto, ON M1C 1A4, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M1C 1A4, Canada; Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada; Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia; Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI 48109, United States; School of Medicine and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, United States; Department of Immunology, University of Toronto, Toronto, ON M1C 1A4, Canada; Center for Scientific Review, NIH, Bethesda, MD 20892, United States
推荐引用方式 GB/T 7714	Jaiswal A.,Murakami K.,Elia A.,et al. Therapeutic inhibition of USP9x-mediated Notch signaling in triple-negative breast cancer[J],2021,118(38).
APA	Jaiswal A..,Murakami K..,Elia A..,Shibahara Y..,Done S.J..,...&Reedijk M..(2021).Therapeutic inhibition of USP9x-mediated Notch signaling in triple-negative breast cancer.Proceedings of the National Academy of Sciences of the United States of America,118(38).
MLA	Jaiswal A.,et al."Therapeutic inhibition of USP9x-mediated Notch signaling in triple-negative breast cancer".Proceedings of the National Academy of Sciences of the United States of America 118.38(2021).