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Norcantharidin promotes cancer radiosensitization through Cullin1 neddylation-mediated CDC6 protein degradation.
- Source :
-
Molecular carcinogenesis [Mol Carcinog] 2022 Aug; Vol. 61 (8), pp. 812-824. Date of Electronic Publication: 2022 Jun 02. - Publication Year :
- 2022
-
Abstract
- Radiotherapy (RT) is a conventional cancer therapeutic modality. However, cancer cells tend to develop radioresistance after a period of treatment. Diagnostic markers and therapeutic targets for radiosensitivity are severely lacking. Our recently published studies demonstrated that the cell division cycle (CDC6) is a critical molecule contributing to radioresistance, and maybe a potential therapeutic target to overcome radioresistance. In the present study, we for the first time reported that Norcantharidin (NCTD), a demethylated form of cantharidin, re-sensitized radioresistant cancer cells to overcome radioresistance, and synergistically promoted irradiation (IR)-induced cell killing and apoptosis by inducing CDC6 protein degradation. Mechanistically, NCTD induced CDC6 protein degradation through the ubiquitin-proteasome pathways. By using small interfering RNA (siRNA) interference or small compound inhibitors, we further determined that NCTD induced CDC6 protein degradation through a neddylation-dependent pathway, but not through Huwe1, Cyclin F, and APC/C-mediated ubiquitin-proteasome pathways. We screened the six most relevant Cullin subunits (CUL1, 2, 3, 4A, 4B, and 5) using siRNAs. The knockdown of Cullin1 but not the other five cullins remarkably elevated CDC6 protein levels. NCTD promoted the binding of Cullin1 to CDC6, thereby promoting CDC6 protein degradation through a Cullin1 neddylation-mediated ubiquitin-proteasome pathway. NCTD can be used in combination with radiotherapy to achieve better anticancer efficacy, or work as a radiosensitizer to overcome cancer radioresistance.<br /> (© 2022 Wiley Periodicals LLC.)
- Subjects :
- Apoptosis
Bridged Bicyclo Compounds, Heterocyclic pharmacology
Cullin Proteins
Humans
Nuclear Proteins metabolism
Proteasome Endopeptidase Complex metabolism
Proteolysis
RNA, Small Interfering metabolism
Tumor Suppressor Proteins metabolism
Ubiquitin-Protein Ligases metabolism
Ubiquitins metabolism
Cell Cycle Proteins metabolism
Neoplasms drug therapy
Neoplasms radiotherapy
Subjects
Details
- Language :
- English
- ISSN :
- 1098-2744
- Volume :
- 61
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Molecular carcinogenesis
- Publication Type :
- Academic Journal
- Accession number :
- 35652616
- Full Text :
- https://doi.org/10.1002/mc.23435