气候变化领域集成服务门户(CCPortal): Δ40p53 isoform up-regulates netrin-1/UNC5B expression and potentiates netrin-1 pro-oncogenic activity

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DOI	10.1073/pnas.2103319118
	Δ40p53 isoform up-regulates netrin-1/UNC5B expression and potentiates netrin-1 pro-oncogenic activity
	Sun Y.; Manceau A.; Frydman L.; Cappuccio L.; Neves D.; Basso V.; Wang H.; Fombonne J.; Maisse C.; Mehlen P.; Paradisi A.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:36
英文摘要	Netrin-1, a secreted protein recently characterized as a relevant cancer therapeutic target, is the antiapoptotic ligand of the dependence receptors deleted in colorectal carcinoma and members of the UNC5H family. Netrin-1 is overexpressed in several aggressive cancers where it promotes cancer progression by inhibiting cell death induced by its receptors. Interference of its binding to its receptors has been shown, through the development of a monoclonal neutralizing antinetrin-1 antibody (currently in phase II of clinical trial), to actively induce apoptosis and tumor growth inhibition. The transcription factor p53was shown to positively regulate netrin-1 gene expression. We show here that netrin-1 could be a target gene of the N-terminal p53 isoform Δ40p53, independent of full-length p53 activity. Using stable cell lines, harboring wild-type or null-p53, in which Δ40p53 expression could be finely tuned, we prove that Δ40p53 binds to and activates the netrin-1 promoter. In addition, we show that forcing immortalized human skeletal myoblasts to produce the Δ40p53 isoform, instead of full-length p53, leads to the up-regulation of netrin-1 and its receptor UNC5B and promotes cell survival. Indeed, we demonstrate that netrin-1 interference, in the presence of Δ40p53, triggers apoptosis in cancer and primary cells, leading to tumor growth inhibition in preclinical in vivo models. Finally, we show a positive correlation between netrin-1 and Δ40p53 gene expression in human melanoma and colorectal cancer biopsies. Hence, we propose that inhibition of netrin- 1 binding to its receptors should be a promising therapeutic strategy in human tumors expressing high levels of Δ40p53. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Apoptosis; Netrin-1; P53 isoform
语种	英语
scopus关键词	delta40p53 isoform; netrin receptor; protein p53; protein UNC5B; unclassified drug; isoprotein; netrin 1; netrin receptor; NTN1 protein, human; protein binding; protein p53; TP53 protein, human; UNC5B protein, human; animal experiment; animal model; apoptosis; Article; cancer inhibition; carcinogenesis; cell survival; colorectal cancer; controlled study; delta40p53 gene; female; gene; gene expression regulation; human; human cell; melanoma; mouse; netrin 1 gene; nonhuman; promoter region; protein DNA binding; protein expression; upregulation; gene silencing; genetics; physiology; tumor cell line; Apoptosis; Carcinogenesis; Cell Line, Tumor; Gene Silencing; Humans; Netrin Receptors; Netrin-1; Promoter Regions, Genetic; Protein Binding; Protein Isoforms; Tumor Suppressor Protein p53; Up-Regulation
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/251026
作者单位	Apoptosis Cancer and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Lyon, 69008, France; Infections Virales et Pathologie Comparée, UMR754 Institut National de la Recherche Agronomique, Université de Lyon, Université Claude Bernard Lyon1, Ecole Pratique des Hautes Etudes, Lyon, 69008, France; Early Development Department, Netris Pharma, Lyon, 69008, France
推荐引用方式 GB/T 7714	Sun Y.,Manceau A.,Frydman L.,et al. Δ40p53 isoform up-regulates netrin-1/UNC5B expression and potentiates netrin-1 pro-oncogenic activity[J],2021,118(36).
APA	Sun Y..,Manceau A..,Frydman L..,Cappuccio L..,Neves D..,...&Paradisi A..(2021).Δ40p53 isoform up-regulates netrin-1/UNC5B expression and potentiates netrin-1 pro-oncogenic activity.Proceedings of the National Academy of Sciences of the United States of America,118(36).
MLA	Sun Y.,et al."Δ40p53 isoform up-regulates netrin-1/UNC5B expression and potentiates netrin-1 pro-oncogenic activity".Proceedings of the National Academy of Sciences of the United States of America 118.36(2021).