Clinicopathological and Functional Evaluation Reveal NBS1 as a Predictor of Platinum Resistance in Epithelial Ovarian Cancers

Alblihy, Adel; Alabdullah, Muslim L.; Ali, Reem; Algethami, Mashael; Toss, Michael S.; Mongan, Nigel P.; Rakha, Emad A.; Madhusudan, Srinivasan

Abstract

Platinum resistance seriously impacts on the survival outcomes of patients with ovarian cancers. Platinum-induced DNA damage is processed through DNA repair. NBS1 is a key DNA repair protein. Here, we evaluated the role of NBS1 in ovarian cancers. NBS1 expression was investigated in clinical cohorts (protein level (n = 331) and at the transcriptomic level (n = 1259)). Pre-clinically, sub-cellular localization of NBS1 at baseline and following cisplatin therapy was tested in platinum resistant (A2780cis, PEO4) and sensitive (A2780, PEO1) ovarian cancer cells. NBS1 was depleted and cisplatin sensitivity was investigated in A2780cis and PEO4 cells. Nuclear NBS1 overexpression was associated with platinum resistance (p = 0.0001). In univariate and multivariate analysis, nuclear NBS1 overexpression was associated with progression free survival (PFS) (p-values = 0.003 and 0.017, respectively) and overall survival (OS) (p-values = 0.035 and 0.009, respectively). NBS1 mRNA overexpression was linked with poor PFS (p = 0.011). Pre-clinically, following cisplatin treatment, we observed nuclear localization of NBS1 in A2780cis and PEO4 compared to A2780 and PEO1 cells. NBS1 depletion increased cisplatin cytotoxicity, which was associated with accumulation of double strand breaks (DSBs), S-phase cell cycle arrest, and increased apoptosis. NBS1 is a predictor of platinum sensitivity and could aid stratification of ovarian cancer therapy.

Citation

Alblihy, A., Alabdullah, M. L., Ali, R., Algethami, M., Toss, M. S., Mongan, N. P., Rakha, E. A., & Madhusudan, S. (2021). Clinicopathological and Functional Evaluation Reveal NBS1 as a Predictor of Platinum Resistance in Epithelial Ovarian Cancers. Biomedicines, 9(1), Article 56. https://doi.org/10.3390/biomedicines9010056

• Journal Article Type: Article
• Acceptance Date: Dec 29, 2020
• Online Publication Date: Jan 8, 2021
• Publication Date: 2021-01
• Deposit Date: Jan 16, 2021
• Publicly Available Date: Jan 18, 2021
• Journal: Biomedicines
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 1
• Article Number: 56
• DOI: https://doi.org/10.3390/biomedicines9010056
• Public URL: https://nottingham-repository.worktribe.com/output/5234550
• Publisher URL: https://www.mdpi.com/2227-9059/9/1/56