SIRT5 Promotes Cisplatin Resistance in Ovarian Cancer by Suppressing DNA Damage in a ROS-Dependent Manner via Regulation of the Nrf2/HO-1 Pathway

Abstract

Sirtuin 5 (SIRT5), a mitochondrial class III NAD-dependent deacetylase, plays controversial roles in tumorigenesis and chemoresistance. Accordingly, its role in ovarian cancer development and drug resistance is not fully understood. Here, we demonstrate that SIRT5 is increased in ovarian cancer tissues compared to its expression in normal tissues and this predicts a poor response to chemotherapy. SIRT5 levels were also found to be higher in cisplatin-resistant SKOV-3 and CAOV-3 ovarian cancer cells than in cisplatin-sensitive A2780 cells. Furthermore, this protein was revealed to facilitate ovarian cancer cell growth and cisplatin-resistance in vitro . Mechanistically, we show that SIRT5 contributes to cisplatin resistance in ovarian cancer by suppressing cisplatin-induced DNA damage in a reactive oxygen species (ROS)-dependent manner via regulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway.

Rosmarinic Acid Methyl Ester Regulates Ovarian Cancer Cell Migration and Reverses Cisplatin Resistance by Inhibiting the Expression of Forkhead Box M1

“…Furthermore, recurrence of ovarian cancer is up to 75% and the recurrent cancer can result in the acquisition of cisplatin resistance, as well [ 43 ]. Thus, cisplatin resistance is a limitation of cisplatin chemotherapy, since there are several molecular mechanisms leading to cisplatin resistance [ 45 , 46 , 47 ]. Among the mechanical reasons, previous studies showed that upregulation of FOXM1 induced cisplatin resistance in several cancer cells [ 48 , 49 , 50 ].…”

Apatinib, a Novel Tyrosine Kinase Inhibitor, Promotes ROS-Dependent Apoptosis and Autophagy via the Nrf2/HO-1 Pathway in Ovarian Cancer Cells

“…Glutathione (GSH). ROS induced by apatinib was determined using a ROS Assay Kit (Beyotime, Shanghai, China) according to the manufacturer's protocol as previously described [16]. Briefly, after exposure to apatinib (0, 10, and 20 μM) for 24 h, the cells were incubated with 10 μM 2 ′ -7 ′ dichlorofluorescin diacetate (DCFH-DA) in the dark for 20 min at 37°C in a humidified atmosphere at 5% CO 2 .…”

“…Oxidative Medicine and Cellular Longevity A Total Glutathione Assay Kit (Beyotime) was used to measure intracellular GSH levels according to the manufacturer's instructions as previously described [16]. Briefly, after being cocultured with or without apatinib for 24 h and/or pretreated with 200 μM TBHQ for 4 h to activate the Nrf2 pathway, cells were harvested and lysed in the protein removal solution S provided in the kit.…”

Advances in DNA Repair—Emerging Players in the Arena of Eukaryotic DNA Repair

“…SIRT4, on the other hand, arrests cell cycle progression in response to DNA damage, providing more time for DNA repair, and thus delaying apoptosis [48]. SIRT5 possesses multiple enzymatic activities but little is known considering its role in DNA repair [49]. The role of sirtuins in DNA repair has been summarized in Figure 2.…”