Ets-1 regulates intracellular glutathione levels: key target for resistant ovarian cancer

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.

Amino Acid Transporters in Cancer and Their Relevance to “Glutamine Addiction”: Novel Targets for the Design of a New Class of Anticancer Drugs

“…Glutamate acts on selective metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs) on cancer cells and potentiates oncogenic signaling (22,23). The relevance of SLC7A11 as a promoter of cancer growth is evident from the findings that the transporter is stabilized in the plasma membrane by a specific cancer-associated variant of CD44 (24) and that the expression of the transporter is induced directly by c-Myc (25) and also by the proto-oncogene Ets-1 (26). This is also supported by several studies, which demonstrate the tumor-suppressing effects of SLC7A11 inhibitors (21).…”

Methionine Dependence of Cancer

“…Indeed, similar redirection of homocysteine into the transsulfuration branch is induced by oncogenic PI3K mutations, which induce a methionine-dependent phenotype when expressed in methionine-independent cells (Figure 2A) [10]. It is interesting to note that the transsulfuration pathway is largely restricted to pancreas, liver, and kidney, but is active in cancer cells [8,[35][36][37], which could contribute to the differential response of cancer cells to growth in homocysteine medium. One can speculate that higher demand for antioxidants like glutathione in cancer may require increased flux through the transsulfuration pathway.…”

“…Biomolecules 2020, 10, x FOR PEER REVIEW 6 of 15 pancreas, liver, and kidney, but is active in cancer cells [8,[35][36][37], which could contribute to the differential response of cancer cells to growth in homocysteine medium. One can speculate that higher demand for antioxidants like glutathione in cancer may require increased flux through the transsulfuration pathway.…”

ETS-1: A potential target of glycolysis for metabolic therapy by regulating glucose metabolism in pancreatic cancer

“…Considerable attention has been paid to ETS-1 due to its important roles in regulating the energy metabolism in cancer cells (11,24). It has been stated that the overexpression of ETS-1 is responsible for the poor prognosis of breast cancer (10,(25)(26)(27)(28)(29)(30)(31), ovarian carcinoma (32)(33)(34), and cervical carcinoma (24,35). Therefore, ETS-1 may be a promising molecular target for the new therapeutic strategy of pancreatic cancer (36).…”