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

• 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
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0236119

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.