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The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells

A 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 evolut...

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Autores principales: Gao, Xiao, Wang, Qingwei, Wang, Ying, Liu, Jiang, Liu, Shuang, Liu, Jian, Zhou, Xingli, Zhou, Li, Chen, Hui, Pan, Linian, Chen, Jiwei, Wang, Da, Zhang, Qing, Shen, Shihui, Xiao, Yu, Wu, Zhipeng, Cheng, Yiyun, Chen, Geng, Krubra, Syeda, Qin, Jun, Huang, Lan, Zhang, Pei, Wang, Chuangui, Moses, Robb E., Lonard, David M., Malley, Bert W. O’, Fares, Fuad, Zhang, Bianhong, Li, Xiaotao, Li, Lei, Xiao, Jianru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413384/
https://www.ncbi.nlm.nih.gov/pubmed/32764536
http://dx.doi.org/10.1038/s41467-020-17667-7
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author Gao, Xiao
Wang, Qingwei
Wang, Ying
Liu, Jiang
Liu, Shuang
Liu, Jian
Zhou, Xingli
Zhou, Li
Chen, Hui
Pan, Linian
Chen, Jiwei
Wang, Da
Zhang, Qing
Shen, Shihui
Xiao, Yu
Wu, Zhipeng
Cheng, Yiyun
Chen, Geng
Krubra, Syeda
Qin, Jun
Huang, Lan
Zhang, Pei
Wang, Chuangui
Moses, Robb E.
Lonard, David M.
Malley, Bert W. O’
Fares, Fuad
Zhang, Bianhong
Li, Xiaotao
Li, Lei
Xiao, Jianru
author_facet Gao, Xiao
Wang, Qingwei
Wang, Ying
Liu, Jiang
Liu, Shuang
Liu, Jian
Zhou, Xingli
Zhou, Li
Chen, Hui
Pan, Linian
Chen, Jiwei
Wang, Da
Zhang, Qing
Shen, Shihui
Xiao, Yu
Wu, Zhipeng
Cheng, Yiyun
Chen, Geng
Krubra, Syeda
Qin, Jun
Huang, Lan
Zhang, Pei
Wang, Chuangui
Moses, Robb E.
Lonard, David M.
Malley, Bert W. O’
Fares, Fuad
Zhang, Bianhong
Li, Xiaotao
Li, Lei
Xiao, Jianru
author_sort Gao, Xiao
collection PubMed
description A 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.
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spelling pubmed-74133842020-08-17 The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells Gao, Xiao Wang, Qingwei Wang, Ying Liu, Jiang Liu, Shuang Liu, Jian Zhou, Xingli Zhou, Li Chen, Hui Pan, Linian Chen, Jiwei Wang, Da Zhang, Qing Shen, Shihui Xiao, Yu Wu, Zhipeng Cheng, Yiyun Chen, Geng Krubra, Syeda Qin, Jun Huang, Lan Zhang, Pei Wang, Chuangui Moses, Robb E. Lonard, David M. Malley, Bert W. O’ Fares, Fuad Zhang, Bianhong Li, Xiaotao Li, Lei Xiao, Jianru Nat Commun Article A 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. Nature Publishing Group UK 2020-08-06 /pmc/articles/PMC7413384/ /pubmed/32764536 http://dx.doi.org/10.1038/s41467-020-17667-7 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Gao, Xiao
Wang, Qingwei
Wang, Ying
Liu, Jiang
Liu, Shuang
Liu, Jian
Zhou, Xingli
Zhou, Li
Chen, Hui
Pan, Linian
Chen, Jiwei
Wang, Da
Zhang, Qing
Shen, Shihui
Xiao, Yu
Wu, Zhipeng
Cheng, Yiyun
Chen, Geng
Krubra, Syeda
Qin, Jun
Huang, Lan
Zhang, Pei
Wang, Chuangui
Moses, Robb E.
Lonard, David M.
Malley, Bert W. O’
Fares, Fuad
Zhang, Bianhong
Li, Xiaotao
Li, Lei
Xiao, Jianru
The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells
title The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells
title_full The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells
title_fullStr The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells
title_full_unstemmed The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells
title_short The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells
title_sort regγ inhibitor nip30 increases sensitivity to chemotherapy in p53-deficient tumor cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413384/
https://www.ncbi.nlm.nih.gov/pubmed/32764536
http://dx.doi.org/10.1038/s41467-020-17667-7
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