HMGB1 assists in overcoming cisplatin resistance in chemoresistant human ovarian cancer cells

Cisplatin is a highly effective chemotherapeutic agent used to treat ovarian cancer, but the development of resistance often limits the treatment outcome. Cisplatin eradicated the cancer cells by generating lethal DNA lesions, which can be recognized and processed by a variety of proteins, including the high mobility group box 1 (HMGB1) protein. HMGB1 is a multifunctional protein, which is involved in chromatin remodeling and DNA damage repair. In this study, we investigated the role of HMGB1 in modulating cisplatin sensitivity in human ovarian cancer cells. Using siRNA-mediated HMGB1 knockdown in cisplatin-sensitive and cisplatin-resistant human ovarian cancer cell lines, we observed that HMGB1 depletion reduced colony formation and enhanced cisplatin-induced apoptosis in the cisplatin-resistant cells. Mechanistically, HMGB1-depleted cells exhibited altered DNA damage responses by mediating the ATM/CHK2 and ATR/CHK1 activity following cisplatin treatment. Slot blot and modified alkaline comet assay further demonstrated that HMGB1 depletion stimulated cisplatin-DNA adduct formation and impaired adduct removal. Collectively, these findings uncover novel functions of HMGB1 in mediating cisplatin sensitivity, emphasizing its potential as a therapeutic target to overcome cisplatin resistance.