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ZZW-115–dependent inhibition of NUPR1 nuclear translocation sensitizes cancer cells to genotoxic agents
Wenjun Lan, … , José L. Neira, Juan Iovanna
Wenjun Lan, … , José L. Neira, Juan Iovanna
Published August 11, 2020
Citation Information: JCI Insight. 2020;5(18):e138117. https://doi.org/10.1172/jci.insight.138117.
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Research Article Cell biology Oncology

ZZW-115–dependent inhibition of NUPR1 nuclear translocation sensitizes cancer cells to genotoxic agents

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Abstract

Establishing the interactome of the cancer-associated stress protein Nuclear Protein 1 (NUPR1), we found that it binds to several hundreds of proteins, including proteins involved in nuclear translocation, DNA repair, and key factors of the SUMO pathway. We demonstrated that the NUPR1 inhibitor ZZW-115, an organic synthetic molecule, competes with importins for the binding to the NLS region of NUPR1, thereby inhibiting its nuclear translocation. We hypothesized, and then proved, that inhibition of NUPR1 by ZZW-115 sensitizes cancer cells to DNA damage induced by several genotoxic agents. Strikingly, we found that treatment with ZZW-115 reduced SUMOylation of several proteins involved in DNA damage response (DDR). We further report that the presence of recombinant NUPR1 improved the SUMOylation in a cell-free system, indicating that NUPR1 directly stimulates the SUMOylation machinery. We propose that ZZW-115 sensitizes cancer cells to genotoxic agents by inhibiting the nuclear translocation of NUPR1 and thereby decreasing the SUMOylation-dependent functions of key proteins involved in the DDR.

Authors

Wenjun Lan, Patricia Santofimia-Castaño, Mirna Swayden, Yi Xia, Zhengwei Zhou, Stephane Audebert, Luc Camoin, Can Huang, Ling Peng, Ana Jiménez-Alesanco, Adrián Velázquez-Campoy, Olga Abián, Gwen Lomberk, Raul Urrutia, Bruno Rizzuti, Vincent Geli, Philippe Soubeyran, José L. Neira, Juan Iovanna

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Figure 4

ZZW-115 strongly potentiated the antitumoral activity of on PDAC genotoxic agents in vivo.

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ZZW-115 strongly potentiated the antitumoral activity of on PDAC genotox...
CAnN.Cg-Foxn1nu/Crl BALB/c nude mice xenografted with MiaPaCa-2 cells were separated into 4 groups of 5 mice and treated daily for 30 days with 0.5% DMSO in physiologic serum (control group), 20 mg/kg 5-FU, 2.5 mg/kg ZZW-115, or 20 mg/kg 5-FU in combination with 2.5 mg/kg ZZW-115. Tumor volume was measured every 3 days. (A and B) Individual volume of each mouse (A) and mean of the volume of each treatment (B) are shown. For each treatment, statistical significance is **P < 0.01 and ***P < 0.001 (1-way ANOVA, Tukey’s post hoc test). (C) Immunostaining of tumor samples with antibodies against Ki67, cleaved caspase-3, and γH2AX. Quantification of foci was performed by ImageJ software on 3 samples of each group. For each treatment, statistical significance is ***P < 0.001, ****P < 0.0001 (1-way ANOVA, Tukey’s post hoc test). Data represent mean ± SEM, n = 3.

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