Abstract
BackgroundOvarian cancer is characterized by high rates of metastasis and therapeutic resistance. Many chemotherapeutic agents rely on the induction of oxidative stress to cause cancer cell death, thus targeting redox regulation is a promising strategy to overcome drug resistance.MethodsWe have used a tetracycline-inducible Ets-1 overexpression model derived from 2008 ovarian cancer cells in the present study. To examine the role of Ets-1 in glutathione regulation we have measured intracellular reactive oxygen species and glutathione levels, as well as glutathione peroxidase enzyme activity. Glutathione synthesis was limited using transsulfuration or Sxc- pathway blocking agents, and glutamate release was measured to confirm Sxc- blockade. Cell viability following drug treatment was assessed via crystal violet assay. Oxidative stress was induced through glucose oxidase treatment, which produces hydrogen peroxide by glucose oxidation. The protein expressions of redox-related factors were measured through western blotting.ResultsOverexpression of Ets-1 was associated with decreased intracellular ROS, concomitantly with increased intracellular GSH, GPX antioxidant activity, and Sxc- transporter activity. Under basal conditions, inhibition of the transsulfuration pathway resulted in decreased GSH levels and GPX activity in all cell lines, whereas inhibition of Sxc- by sulfasalazine decreased GPX activity in Ets-1-expressing cells only. However, under oxidative stress the intracellular GSH levels decreased significantly in correlation with increased Ets-1 expression following sulfasalazine treatment.ConclusionsIn this study we have identified a role for proto-oncogene Ets-1 in the regulation of intracellular glutathione levels, and examined the effects of the anti-inflammatory drug sulfasalazine on glutathione depletion using an ovarian cancer cell model. The findings from this study show that Ets-1 mediates enhanced Sxc- activity to increase glutathione levels under oxidative stress, suggesting that Ets-1 could be a promising putative target to enhance conventional therapeutic strategies.
Highlights
Ovarian cancer is characterized by high rates of metastasis and therapeutic resistance
Our results show that V-ets erythroblastosis virus E26 oncogene homolog 1 (Ets-1) mediates enhanced Sxc- activity to increase glutathione recycling in ovarian cancer cells, and that this effect was enhanced during oxidative stress
Ets-1 decreases intracellular reactive oxygen species (ROS), while increasing intracellular Reduced glutathione (GSH) and glutathione peroxidase (GPX) activity To examine the role of Ets-1 in the regulation of cellular antioxidant capacity, we measured intracellular ROS levels, total cellular GSH, and GPX enzyme activity
Summary
Ovarian cancer is characterized by high rates of metastasis and therapeutic resistance. Cancer stem cells have been revealed as a key cell type involved in the recurrence and drug resistance of ovarian cancer [2,3,4,5,6]. Due to the heterogeneous nature of ovarian cancer tumors, it is thought that primary tumours are composed of drug sensitive cells, resistant cells, and cancer initiating stem cells. In this theory, the bulk of primary tumours are composed of sensitive cells that succumb to initial chemotherapy treatment, the population of cancer stem cells that are drug resistant repopulate the tumour resulting in drug resistance upon recurrence
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