HMGB2 Impacts Cisplatin-Induced DNA Adduct Processing in Chemoresistant Ovarian Cancer Cells

Background/Objectives: Cisplatin is used in the treatment of ovarian cancer; however, the development of resistance, often due to the efficient repair of cisplatin-induced DNA damage, remains a major barrier to effective therapy. Among these lesions, DNA interstrand crosslinks (ICLs) are particularly cytotoxic because they prevent DNA replication and transcription. HMGB2, a member of the high-mobility group box (HMGB) protein family, can bind DNA lesions and has been implicated in genome maintenance and DNA repair. This study investigated whether HMGB2 contributes to the processing of cisplatin-induced DNA damage and modulates cisplatin sensitivity in human ovarian cancer cells. Methods: HMGB2 expression was suppressed by siRNA in cisplatin-sensitive A2780 and cisplatin-resistant CP70 human ovarian cancer cells. Cellular responses to cisplatin were assessed using clonogenic survival assays, cell cycle analysis, Western blotting, slot blot analysis, and modified alkaline comet assays. Results: HMGB2 depletion reduced clonogenic survival in cisplatin-resistant CP70 cells and increased the sub-G1 population, indicating enhanced apoptotic DNA fragmentation following cisplatin treatment in both cell lines. Depletion of HMGB2 resulted in increased persistence of cisplatin-DNA adducts and impaired ICL processing, as demonstrated by persistent DNA damage over time and reduced ICL unhooking efficiency. DNA damage response signaling following cisplatin treatment was also altered by HMGB2 depletion in both cell lines, whereas the expression levels of key DNA repair proteins were unchanged. Conclusions: Our findings demonstrate that HMGB2 is involved in the cellular response to cisplatin treatment by promoting the efficient processing of cisplatin DNA adducts, particularly ICLs, thereby modulating cisplatin sensitivity in human ovarian cancer cells. These findings suggest that targeting HMGB2 may serve as a potential therapeutic strategy for overcoming cisplatin resistance in ovarian cancer.