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

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  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science
    • Subject Terms:
      Carcinoma, Renal Cell/*drug therapy ; Disulfiram/*pharmacology ; Drug Repositioning/*methods ; Drug Resistance, Neoplasm/*drug effects ; Kidney Neoplasms/*drug therapy ; Nuclear Proteins/*antagonists & inhibitors; Acetaldehyde Dehydrogenase Inhibitors/pharmacology ; Animals ; Apoptosis ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Carcinoma, Renal Cell/metabolism ; Carcinoma, Renal Cell/pathology ; Cell Proliferation ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Kidney Neoplasms/metabolism ; Kidney Neoplasms/pathology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Prognosis ; RNA, Small Interfering/genetics ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
    • Abstract:
      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.
      Competing Interests: The authors have declared that no competing interests exist.
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    • Accession Number:
      0 (Acetaldehyde Dehydrogenase Inhibitors)
      0 (Biomarkers, Tumor)
      0 (NPLOC4 protein, human)
      0 (Nuclear Proteins)
      0 (RNA, Small Interfering)
      TR3MLJ1UAI (Disulfiram)
    • Publication Date:
      Date Created: 20200716 Date Completed: 20200917 Latest Revision: 20200917
    • Publication Date:
      20240105
    • Accession Number:
      PMC7363112
    • Accession Number:
      10.1371/journal.pone.0236119
    • Accession Number:
      32667929