Abstract
Cisplatin resistance remains a significant obstacle for improving the clinical outcome of ovarian cancer patients. Recent studies have demonstrated that cisplatin is an important inducer of intracellullar reactive oxygen species (ROS), triggering cancer cell death. Sirtuin 2 (SIRT2), a member of class III NAD+ dependent histone deacetylases (HDACs), has been reported to be involved in regulating cancer hallmarks including drug response. In this study, we aimed to identify the role of SIRT2 in oxidative stress and cisplatin response in cancer. Two ovarian cancer cell lines featuring different sensitivities to cisplatin were used in this study. We found different expression patterns of SIRT2 in cisplatin-sensitive (A2780/S) and cisplatin-resistant (A2780/CP) cancer cells with cisplatin treatment, where SIRT2 expression was augmented only in A2780/S cells. Furthermore, cisplatin-induced ROS generation was responsible for the upregulation of SIRT2 in A2780/S cells, whereas overexpression of SIRT2 significantly enhanced the sensitivity of cisplatin-resistant counterpart cells to cisplatin. Our study proposes that targeting SIRT2 may provide new strategies to potentiate platinum-based chemotherapy in ovarian cancer patients.
Highlights
Ovarian cancer is the most lethal gynecologic cancer in women worldwide [1]
We investigated the differential regulation of Sirtuin 2 (SIRT2) expression in response to cisplatin treatment in A2780/S and A2780/CP ovarian cancer cell lines
We found that cisplatin-induced reactive oxygen species (ROS) generation was responsible for the upregulation of SIRT2 in A2780/CP cells
Summary
Ovarian cancer is the most lethal gynecologic cancer in women worldwide [1]. Most patients are diagnosed at advanced stages largely due to the absence of specific symptoms and lack of early diagnostic markers [2,3]. The standard treatment of ovarian cancer currently is debulking surgery followed by platinum-based chemotherapy. Up to 70% of patients experience relapses as a result of chemoresistance [4]. There has only been a very modest improvement in the survival of ovarian cancer patients over the past decades, with the five-year survival rate under 45% [5]. Understanding cisplatin resistance mechanisms is of great significance for improving the clinical outcome of ovarian cancer patients
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