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CEP131 Abrogates CHK1 Inhibitor-Induced Replication Defects and Is Associated with Unfavorable Outcome in
Kiyohiro Ando1,2,3,4,5, Verna Cázares-Ordoñez4, Makoto Makishima4
1Department of Clinical Diagnostic Oncology, Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, 6-11-11 Kita-Karasuyama, Setagaya-ku, Tokyo 157-8577, Japan.
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.
Insights
Checkpoint kinase 1 inhibitors (CHK1i) can cause DNA damage in neuroblastoma cells. However, increased MDM2 oncogene expression and CEP131 protein can lead to resistance, suggesting CEP131 as a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Checkpoint kinase 1 (CHK1) is crucial for cell cycle regulation and genome stability.
- CHK1 inhibitors (CHK1i) are being investigated as cancer treatments, including for neuroblastoma.
- Previous research showed CHK1i can induce a p53-mediated DNA damage response, leading to resistance.
Purpose of the Study:
- To investigate the mechanisms of CHK1 inhibitor resistance in neuroblastoma.
- To identify novel therapeutic targets for neuroblastoma treatment.
Main Methods:
- Utilized neuroblastoma cell lines (NB-39-nu) treated with CHK1 inhibitor PF-477736.
- Performed mass spectrometry to identify proteins interacting with MDM2.
- Analyzed CEP131 expression and its correlation with patient prognosis.
Main Results:
- PF-477736 increased MDM2 oncogene expression and replication defects in neuroblastoma cells.
- CEP131 was identified as a binding partner of MDM2.
- MDM2 facilitates CEP131 degradation; CEP131 overexpression promotes neuroblastoma growth and CHK1i resistance.
Conclusions:
- CEP131 plays a role in neuroblastoma cell proliferation and resistance to CHK1 inhibitors.
- Targeting CEP131 may offer a new therapeutic strategy for neuroblastoma.
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