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GSTZ1 expression and chloride concentrations modulate sensitivity of cancer cells to dichloroacetate
Stephan C Jahn1, Mohamed Hassan M Solayman2, Ryan J Lorenzo1
1Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, United States.
Abstract:
Dichloroacetate (DCA), commonly used to treat metabolic disorders, is under investigation as an anti-cancer therapy due to its ability to reverse the Warburg effect and induce apoptosis in tumor cells. While DCA's mechanism of action is well-studied, other factors that influence its potential as a cancer treatment have not been thoroughly investigated. Here we show that expression of glutathione transferase zeta 1 (GSTZ1), the enzyme responsible for conversion of DCA to its inactive metabolite, glyoxylate, is downregulated in liver cancer and upregulated in some breast cancers, leading to abnormal expression of the protein. The cellular concentration of chloride, an ion that influences the stability of GSTZ1 in the presence of DCA, was also found to be abnormal in tumors, with consistently higher concentrations in hepatocellular carcinoma than in surrounding non-tumor tissue. Finally, results from experiments employing two- and three-dimensional cultures of HepG2 cells, parental and transduced to express GSTZ1, demonstrate that high levels of GSTZ1 expression confers resistance to the effect of high concentrations of DCA on cell viability. These results may have important clinical implications in determining intratumoral metabolism of DCA and, consequently, appropriate oral dosing.
Insights
Dichloroacetate (DCA) shows anti-cancer potential by reversing the Warburg effect. Glutathione transferase zeta 1 (GSTZ1) expression and chloride levels influence DCA
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Dichloroacetate (DCA) is investigated for anti-cancer properties, targeting the Warburg effect and inducing apoptosis.
- While DCA's anti-cancer mechanisms are known, factors influencing its efficacy require further study.
- Glutathione transferase zeta 1 (GSTZ1) metabolizes DCA; its role in cancer and DCA efficacy is unclear.
Purpose of the Study:
- To investigate the role of glutathione transferase zeta 1 (GSTZ1) and chloride levels in the anti-cancer effects of dichloroacetate (DCA).
- To determine how GSTZ1 expression and cellular chloride concentration impact DCA's efficacy in liver and breast cancer models.
Main Methods:
- Analysis of GSTZ1 expression in liver and breast cancer tissues.
- Measurement of intracellular chloride concentrations in hepatocellular carcinoma.
- Experiments with HepG2 cells (parental and GSTZ1-expressing) in 2D and 3D cultures treated with DCA.
Main Results:
- GSTZ1 expression is downregulated in liver cancer and upregulated in some breast cancers.
- Hepatocellular carcinoma exhibits higher intracellular chloride concentrations than adjacent non-tumor tissue.
- High GSTZ1 expression in HepG2 cells confers resistance to high DCA concentrations, affecting cell viability.
Conclusions:
- GSTZ1 expression and chloride levels are altered in tumors, influencing DCA metabolism.
- These findings suggest that intratumoral GSTZ1 levels and chloride concentrations are critical for determining effective DCA dosing in cancer therapy.
