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The REG? inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells.

ABSTRACT: A major challenge in chemotherapy is chemotherapy resistance in cells lacking p53. Here we demonstrate that NIP30, an inhibitor of the oncogenic REG?-proteasome, attenuates cancer cell growth and sensitizes p53-compromised cells to chemotherapeutic agents. NIP30 acts by binding to REG? 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 REG? activity during the cell cycle or after DNA damage. We validate CDC25A-NIP30-REG? mediated regulation of the REG? target protein p21 in vivo using p53-/- and p53/REG? 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 REG?-proteasome in carcinogenesis and offer a novel approach to drug-resistant cancer therapy.

SUBMITTER: Gao X

PROVIDER: S-EPMC7413384 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Gao Xiao X Wang Qingwei Q Wang Ying Y Liu Jiang J Liu Shuang S Liu Jian J Zhou Xingli X Zhou Li L Chen Hui H Pan Linian L Chen Jiwei J Wang Da D Zhang Qing Q Shen Shihui S Xiao Yu Y Wu Zhipeng Z Cheng Yiyun Y Chen Geng G Kubra Syeda S Qin Jun J Huang Lan L Zhang Pei P Wang Chuangui C Moses Robb E RE Lonard David M DM Malley Bert W O' BWO Fares Fuad F Zhang Bianhong B Li Xiaotao X Li Lei L Xiao Jianru J

Nature communications 20200806 1

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 ...[more]

PMID: 32764536

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Project description:Studies of radiation interaction with tumor cells often focus on apoptosis as an end point; however, clinically relevant doses of radiation also promote autophagy and senescence. Moreover, functional p53 has frequently been implicated in contributing to radiation sensitivity through the facilitation of apoptosis. To address the involvement of apoptosis, autophagy, senescence and p53 status in the response to radiation, the current studies utilized isogenic H460 non-small cell lung cancer cells that were either p53-wild type (H460wt) or null (H460crp53). As anticipated, radiosensitivity was higher in the H460wt cells than in the H460crp53 cell line; however, this differential radiation sensitivity did not appear to be a consequence of apoptosis. Furthermore, radiosensitivity did not appear to be reduced in association with the promotion of autophagy, as autophagy was markedly higher in the H460wt cells. Despite radiosensitization by chloroquine in the H460wt cells, the radiation-induced autophagy proved to be essentially nonprotective, as inhibition of autophagy via 3-methyl adenine (3-MA), bafilomycin A1 or ATG5 silencing failed to alter radiation sensitivity or promote apoptosis in either the H460wt or H460crp53 cells. Radiosensitivity appeared to be most closely associated with senescence, which occurred earlier and to a greater extent in the H460wt cells. This finding is consistent with the in-depth proteomics analysis on the secretomes from the H460wt and H460crp53 cells (with or without radiation exposure) that showed no significant association with radioresistance-related proteins, whereas several senescence-associated secretory phenotype (SASP) factors were upregulated in H460wt cells relative to H460crp53 cells. Taken together, these findings indicate that senescence, rather than apoptosis, plays a central role in determination of radiosensitivity; furthermore, autophagy is likely to have minimal influence on radiosensitivity under conditions where autophagy takes the nonprotective form.

Dataset Information

The REG? inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells.

Publications

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

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