Abstract
Intrinsic or acquired resistance seriously limits the use of platinating agents in advanced epithelial ovarian cancers. Increased DNA repair capacity is a key route to platinum resistance. RAD50 is a critical component of the MRN complex, a ‘first responder’ to DNA damage and essential for the repair of DSBs and stalled replication forks. We hypothesised a role for RAD50 in ovarian cancer pathogenesis and therapeutics. Clinicopathological significance of RAD50 expression was evaluated in clinical cohorts of ovarian cancer at the protein level (n = 331) and at the transcriptomic level (n = 1259). Sub-cellular localization of RAD50 at baseline and following cisplatin therapy was tested in platinum resistant (A2780cis, PEO4) and sensitive (A2780, PEO1) ovarian cancer cells. RAD50 was depleted and cisplatin sensitivity was investigated in A2780cis and PEO4 cells. RAD50 deficiency was associated with better progression free survival (PFS) at the protein (p = 0.006) and transcriptomic level (p < 0.001). Basal level of RAD50 was higher in platinum resistant cells. Following cisplatin treatment, increased nuclear localization of RAD50 was evident in A2780cis and PEO4 compared to A2780 and PEO1 cells. RAD50 depletion using siRNAs in A2780cis and PEO4 cells increased cisplatin cytotoxicity, which was associated with accumulation of DSBs, S-phase cell cycle arrest and increased apoptosis. We provide evidence that RAD50 deficiency is a predictor of platinum sensitivity. RAD50 expression-based stratification and personalization could be viable clinical strategy in ovarian cancers.
Highlights
Platinating agents such as cisplatin and carboplatin are commonly used in the treatment of ovarian cancer
Low RAD50 expression was associated with better progression free survival (PFS) (p = 0.006) (Fig. 1b) and better overall survival (OS) (p = 0.003) (Fig. 1c)
We provide evidence that RAD50 expression is a predictor of platinum sensitivity
Summary
Platinating agents such as cisplatin and carboplatin are commonly used in the treatment of ovarian cancer. The MRE11-RAD50-NBS1 (MRN) complex is a ‘first responder’ to DNA damage and is essential for the repair of DSBs and stalled replication forks [9]. RAD50 is (2020) 1:19 a core protein of MRN complex. RAD50 is an ATP-modulated DNA cross-linker that has three vital domains: ATP-binding cassette (ABC), zink hook region and MRE11 interaction site [12], and the integrity of these domains is crucial for the process of DSBs by the MRN complex [13]. RAD50 acts as a bridge at the junction of DNA damage, facilitating the recognition and processing of DNA ends by the exonuclease activity of MRE11 to initiate DNA repair. RAD50 polymorphisms are associated with increased risk of breast and ovarian cancer [18]
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