Work

The central role of NADPH depletion in MnTE-2-PyP-induced prostate cancer cell growth inhibition

Year: 2021

Type: article

Abstract: Radiotherapy is commonly used in prostate cancer treatment. MnTE-2-PyP is a superoxide dismutase (SOD) mimic that can protect normal tissues from radiation toxicities while simultaneously promoting radiation-induced damage to cancer tissues. Previous work from our laboratory demonstrated that MnTE-2-PyP increased cellular H 2 O 2 levels and led to protein oxidation and DNA damage in prostate cancer cells, which partially contributes to prostate cancer growth arrest. However, the central mechanisms by which MnTE-2-PyP reduces prostate cancer growth remain unclear. In this study, we identified that MnTE-2-PyP depleted cellular reductant levels, especially NADPH, in prostate cancer cells. Correspondingly, we observed a significant decrease in activity of glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD), which are major cellular NADPH producing enzymes in the pentose phosphate pathway. A decrease of GSH/GSSG ratios were confirmed in MnTE-2-PyP-treated prostate cancer cells, which may result from the decreased glutathione reductase (GR) activity due to NADPH depletion. We also identified that MnTE-2-PyP with radiation significantly increased lipid peroxidation in prostate cancer cells and upregulated sphingomyelin synthesis, which could further consume available NADPH. Thus, MnTE-2-PyP treatment causes lower NADPH levels, resulting in more oxidative stress and membrane damage of prostate cancer cells.

Source: Advances in Redox Research

DOI: 10.1016/j.arres.2021.100025