N-myc downstream-regulated gene 1 promotes oxaliplatin-triggered apoptosis in colorectal cancer cells via enhancing the ubiquitination of Bcl-2.

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  • Additional Information
    • Source:
      Publisher: Impact Journals Country of Publication: United States NLM ID: 101532965 Publication Model: Print Cited Medium: Internet ISSN: 1949-2553 (Electronic) Linking ISSN: 19492553 NLM ISO Abbreviation: Oncotarget Subsets: MEDLINE
    • Publication Information:
      Original Publication: Albany, N.Y. : Impact Journals
    • Subject Terms:
      Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Cell Cycle Proteins/*metabolism ; Colorectal Neoplasms/*metabolism ; Intracellular Signaling Peptides and Proteins/*metabolism ; Organoplatinum Compounds/*pharmacology ; Proto-Oncogene Proteins c-bcl-2/*metabolism; Aged ; Aged, 80 and over ; Animals ; Apoptosis/genetics ; Cell Cycle Proteins/genetics ; Cell Line, Tumor ; Cell Proliferation ; Chemotherapy, Adjuvant ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/mortality ; Colorectal Neoplasms/pathology ; Disease Models, Animal ; Female ; Gene Expression ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Male ; Mice ; Middle Aged ; Neoplasm Metastasis ; Neoplasm Staging ; Oxaliplatin ; Prognosis ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; Protein Kinase C-alpha/metabolism ; Signal Transduction ; Treatment Outcome ; Tumor Burden ; Ubiquitination ; Ubiquitins/metabolism ; Xenograft Model Antitumor Assays
    • Abstract:
      N-myc downstream-regulated gene1 (NDRG1) has been identified as a potent tumor suppressor gene. The molecular mechanisms of anti-tumor activity of NDRG1 involve its suppressive effects on a variety of tumorigenic signaling pathways. The purpose of this study was to investigate the role of NDRG1 in the apoptosis of colorectal cancer (CRC) cells. We first collected the clinical data of locally advanced rectal cancer (LARC) patients receiving oxaliplatin-based neoadjuvant chemotherapy in our medical center. Correlation analysis revealed that NDRG1 positively associated with the downstaging rates and prognosis of patients. Then, the effects of over-expression and depletion of NDRG1 gene on apoptosis of colorectal cancer were tested in vitro and in vivo. NDRG1 over-expression promoted apoptosis in colorectal cancer cells whereas depletion of NDRG1 resulted in resistance to oxaliplatin treatment. Furthermore, we observed that Bcl-2, a major anti-apoptotic protein, was regulated by NDRG1 at post-transcriptional level. By binding Protein kinase Cα (PKCα), a classical regulating factor of Bcl-2, NDRG1 enhanced the ubiquitination and degradation of Bcl-2, thus promoting apoptosis in CRC cells. In addition, NDRG1 inhibited tumor growth and promoted apoptosis in mouse xenograft model. In conclusion,NDRG1 promotes oxaliplatin-triggered apoptosis in colorectal cancer. Therefore, colorectal cancer patients can be stratified by the expression level of NDRG1. NDRG1-positive patients may benefit from oxaliplatin-containing chemotherapy regimens whereas those with negative NDRG1 expression should avoid the usage of this cytotoxic drug.
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    • Contributed Indexing:
      Keywords: Bcl-2; NDRG1; apoptosis; colorectal cancer; neoadjuvant chemotherapy
    • Accession Number:
      0 (Antineoplastic Agents)
      0 (Cell Cycle Proteins)
      0 (Intracellular Signaling Peptides and Proteins)
      0 (N-myc downstream-regulated gene 1 protein)
      0 (Organoplatinum Compounds)
      0 (Proto-Oncogene Proteins c-bcl-2)
      0 (Ubiquitins)
      04ZR38536J (Oxaliplatin)
      EC 2.7.11.13 (Protein Kinase C-alpha)
      EC 3.4.25.1 (Proteasome Endopeptidase Complex)
    • Publication Date:
      Date Created: 20170525 Date Completed: 20180423 Latest Revision: 20220409
    • Publication Date:
      20221213
    • Accession Number:
      PMC5564599
    • Accession Number:
      10.18632/oncotarget.17711
    • Accession Number:
      28537875