Targeting NPL4 via drug repositioning using disulfiram for the treatment of clear cell renal cell carcinoma

The alcohol-abuse drug disulfiram has antitumor effects against diverse cancer types via inhibition of the ubiquitin-proteasome protein nuclear protein localization protein 4 (NPL4). However, the antitumor effects of NPL4 and disulfiram in clear cell renal cell carcinoma (ccRCC) are unclear. Here, w...

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Published in:PloS one 2020-07, Vol.15 (7), p.e0236119-e0236119
Main Authors: Yoshino, Hirofumi, Yamada, Yasutoshi, Enokida, Hideki, Osako, Yoichi, Tsuruda, Masafumi, Kuroshima, Kazuki, Sakaguchi, Takashi, Sugita, Satoshi, Tatarano, Shuichi, Nakagawa, Masayuki
Format: Article
Language:English
Subjects:
Alcohol abuse
Aldehyde reductase
Antibodies
Anticancer properties
Antitumor activity
Apoptosis
Biology and Life Sciences
Biosynthesis
Cancer
Cell adhesion & migration
Cell growth
Cell proliferation
Clear cell-type renal cell carcinoma
Disulfiram
Drug abuse
Drug therapy
Enzymes
Experiments
Gene expression
Genomes
Health aspects
Kidney cancer
Kinases
Localization
Medicine and Health Sciences
Metabolism
Metabolites
Methods
Molecular targeted therapy
Patients
Proteasomes
Proteins
Reductases
Renal cell carcinoma
RNA-mediated interference
Serine
siRNA
Survival analysis
Ubiquitin
Ubiquitin-proteasome system
Urology
Xenografts
Xenotransplantation
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cited_by cdi_FETCH-LOGICAL-c735t-24492fd41527fd8dfc3875e9ac637fabb3f383a9c56a58ce5cc8e7e5eb88d30f3
cites cdi_FETCH-LOGICAL-c735t-24492fd41527fd8dfc3875e9ac637fabb3f383a9c56a58ce5cc8e7e5eb88d30f3
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creator Yoshino, Hirofumi
Yamada, Yasutoshi
Enokida, Hideki
Osako, Yoichi
Tsuruda, Masafumi
Kuroshima, Kazuki
Sakaguchi, Takashi
Sugita, Satoshi
Tatarano, Shuichi
Nakagawa, Masayuki
description The alcohol-abuse drug disulfiram has antitumor effects against diverse cancer types via inhibition of the ubiquitin-proteasome protein nuclear protein localization protein 4 (NPL4). However, the antitumor effects of NPL4 and disulfiram in clear cell renal cell carcinoma (ccRCC) are unclear. Here, we evaluated the therapeutic potential of targeting the ubiquitin-proteasome pathway using disulfiram and RNA interference and investigated the mechanisms underlying disulfiram in ccRCC. According to data from The Cancer Genome Atlas, NPL4 mRNA expression was significantly upregulated in clinical ccRCC samples compared with that in normal kidney samples, and patients with high NPL4 expression had poor overall survival compared with patients with low NPL4 expression. Disulfiram and NPL4 siRNA inhibited ccRCC cell proliferation in vitro, and disulfiram inhibited ccRCC tumor growth in a xenograft model. Synergistic antiproliferative effects were observed for combination treatment with disulfiram and sunitinib in vitro and in vivo. In RCC cells from mice treated with disulfiram and/or sunitinib, several genes associated with serine biosynthesis and aldose reductase were downregulated in cells treated with disulfiram or sunitinib alone and further downregulated in cells treated with both disulfiram and sunitinib. These findings provided insights into the mechanisms of disulfiram and suggested novel therapeutic strategies for RCC treatment.
doi_str_mv 10.1371/journal.pone.0236119
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However, the antitumor effects of NPL4 and disulfiram in clear cell renal cell carcinoma (ccRCC) are unclear. Here, we evaluated the therapeutic potential of targeting the ubiquitin-proteasome pathway using disulfiram and RNA interference and investigated the mechanisms underlying disulfiram in ccRCC. According to data from The Cancer Genome Atlas, NPL4 mRNA expression was significantly upregulated in clinical ccRCC samples compared with that in normal kidney samples, and patients with high NPL4 expression had poor overall survival compared with patients with low NPL4 expression. Disulfiram and NPL4 siRNA inhibited ccRCC cell proliferation in vitro, and disulfiram inhibited ccRCC tumor growth in a xenograft model. Synergistic antiproliferative effects were observed for combination treatment with disulfiram and sunitinib in vitro and in vivo. In RCC cells from mice treated with disulfiram and/or sunitinib, several genes associated with serine biosynthesis and aldose reductase were downregulated in cells treated with disulfiram or sunitinib alone and further downregulated in cells treated with both disulfiram and sunitinib. These findings provided insights into the mechanisms of disulfiram and suggested novel therapeutic strategies for RCC treatment.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>32667929</pmid><doi>10.1371/journal.pone.0236119</doi><tpages>e0236119</tpages><orcidid>https://orcid.org/0000-0003-4224-5084</orcidid><orcidid>https://orcid.org/0000-0002-3050-9700</orcidid><oa>free_for_read</oa></addata></record>
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subjects Alcohol abuse
Aldehyde reductase
Antibodies
Anticancer properties
Antitumor activity
Apoptosis
Biology and Life Sciences
Biosynthesis
Cancer
Cell adhesion & migration
Cell growth
Cell proliferation
Clear cell-type renal cell carcinoma
Disulfiram
Drug abuse
Drug therapy
Enzymes
Experiments
Gene expression
Genomes
Health aspects
Kidney cancer
Kinases
Localization
Medicine and Health Sciences
Metabolism
Metabolites
Methods
Molecular targeted therapy
Patients
Proteasomes
Proteins
Reductases
Renal cell carcinoma
RNA-mediated interference
Serine
siRNA
Survival analysis
Ubiquitin
Ubiquitin-proteasome system
Urology
Xenografts
Xenotransplantation
title Targeting NPL4 via drug repositioning using disulfiram for the treatment of clear cell renal cell carcinoma
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