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CEP131 Abrogates CHK1 Inhibitor-Induced Replication Defects and Is Associated with Unfavorable Outcome in Neuroblastoma
- Source :
- Journal of Oncology, Vol 2020 (2020)
- Publication Year :
- 2020
- Publisher :
- Hindawi, 2020.
-
Abstract
- Checkpoint kinase 1 (CHK1) plays a key role in genome surveillance and integrity throughout the cell cycle. Selective inhibitors of CHK1 (CHK1i) are undergoing clinical evaluation for various human malignancies, including neuroblastoma. Recently, we reported that CHK1i, PF-477736, induced a p53-mediated DNA damage response. As a result, the cancer cells were able to repair DNA damage and became less sensitive to CHK1i. In this study, we discovered that PF-477736 increased expression of MDM2 oncogene along with CHK1i-induced replication defects in neuroblastoma NB-39-nu cells. A mass spectrometry analysis of protein binding to MDM2 in the presence of CHK1i identified the centrosome-associated family protein 131 (CEP131), which was correlated with unfavorable prognosis of neuroblastoma patients. We revealed that MDM2 was associated with CEP131 protein degradation, whereas overexpression of CEP131 accelerated neuroblastoma cell growth and exhibited resistance to CHK1i-induced replication defects. Thus, these findings may provide a future therapeutic strategy against centrosome-associated oncogenes involving CEP131 as a target in neuroblastoma.
- Subjects :
- 0301 basic medicine
biology
Oncogene
Article Subject
business.industry
DNA damage
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Cell cycle
Protein degradation
medicine.disease
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
Oncology
030220 oncology & carcinogenesis
Neuroblastoma
Cancer cell
Cancer research
biology.protein
Medicine
Mdm2
CHEK1
business
neoplasms
RC254-282
Subjects
Details
- Language :
- English
- ISSN :
- 16878450
- Database :
- OpenAIRE
- Journal :
- Journal of Oncology
- Accession number :
- edsair.doi.dedup.....1320fe9d712314aa07865d20cae17c96
- Full Text :
- https://doi.org/10.1155/2020/2752417