The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells
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Published:2020-08-06
Issue:1
Volume:11
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Gao Xiao, Wang Qingwei, Wang Ying, Liu Jiang, Liu Shuang, Liu JianORCID, Zhou Xingli, Zhou Li, Chen Hui, Pan Linian, Chen Jiwei, Wang Da, Zhang Qing, Shen Shihui, Xiao Yu, Wu Zhipeng, Cheng Yiyun, Chen GengORCID, Kubra Syeda, Qin Jun, Huang LanORCID, Zhang Pei, Wang Chuangui, Moses Robb E., Lonard David M., Malley Bert W. O’ORCID, Fares Fuad, Zhang Bianhong, Li Xiaotao, Li LeiORCID, Xiao Jianru
Abstract
AbstractA major challenge in chemotherapy is chemotherapy resistance in cells lacking p53. Here we demonstrate that NIP30, an inhibitor of the oncogenic REGγ-proteasome, attenuates cancer cell growth and sensitizes p53-compromised cells to chemotherapeutic agents. NIP30 acts by binding to REGγ via an evolutionarily-conserved serine-rich domain with 4-serine phosphorylation. We find the cyclin-dependent phosphatase CDC25A is a key regulator for NIP30 phosphorylation and modulation of REGγ activity during the cell cycle or after DNA damage. We validate CDC25A-NIP30-REGγ mediated regulation of the REGγ target protein p21 in vivo using p53−/− and p53/REGγ double-deficient mice. Moreover, Phosphor-NIP30 mimetics significantly increase the growth inhibitory effect of chemotherapeutic agents in vitro and in vivo. Given that NIP30 is frequently mutated in the TCGA cancer database, our results provide insight into the regulatory pathway controlling the REGγ-proteasome in carcinogenesis and offer a novel approach to drug-resistant cancer therapy.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference48 articles.
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