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

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...

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Autores principales:	Yuxiang Zhu, Divya Murthy, Sai Sundeep Kollala, Elizabeth A. Kosmacek, Arpita Chatterjee, Joshua A. McDowell, Pankaj K. Singh, Rebecca E. Oberley-Deegan
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Mn porphyrins MnTE-2-PyP Prostate cancer Metabolism NADPH Sphingomyelin Biochemistry QD415-436
Acceso en línea:	https://doaj.org/article/c88a430211594c2db68f4a6a08566a9f
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spelling	oai:doaj.org-article:c88a430211594c2db68f4a6a08566a9f2021-12-02T05:04:36ZThe central role of NADPH depletion in MnTE-2-PyP-induced prostate cancer cell growth inhibition2667-137910.1016/j.arres.2021.100025https://doaj.org/article/c88a430211594c2db68f4a6a08566a9f2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2667137921000254https://doaj.org/toc/2667-1379Radiotherapy 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 H2O2 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.Yuxiang ZhuDivya MurthySai Sundeep KollalaElizabeth A. KosmacekArpita ChatterjeeJoshua A. McDowellPankaj K. SinghRebecca E. Oberley-DeeganElsevierarticleMn porphyrinsMnTE-2-PyPProstate cancerMetabolismNADPHSphingomyelinBiochemistryQD415-436ENAdvances in Redox Research, Vol 3, Iss , Pp 100025- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mn porphyrins MnTE-2-PyP Prostate cancer Metabolism NADPH Sphingomyelin Biochemistry QD415-436
spellingShingle	Mn porphyrins MnTE-2-PyP Prostate cancer Metabolism NADPH Sphingomyelin Biochemistry QD415-436 Yuxiang Zhu Divya Murthy Sai Sundeep Kollala Elizabeth A. Kosmacek Arpita Chatterjee Joshua A. McDowell Pankaj K. Singh Rebecca E. Oberley-Deegan The central role of NADPH depletion in MnTE-2-PyP-induced prostate cancer cell growth inhibition
description	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 H2O2 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.
format	article
author	Yuxiang Zhu Divya Murthy Sai Sundeep Kollala Elizabeth A. Kosmacek Arpita Chatterjee Joshua A. McDowell Pankaj K. Singh Rebecca E. Oberley-Deegan
author_facet	Yuxiang Zhu Divya Murthy Sai Sundeep Kollala Elizabeth A. Kosmacek Arpita Chatterjee Joshua A. McDowell Pankaj K. Singh Rebecca E. Oberley-Deegan
author_sort	Yuxiang Zhu
title	The central role of NADPH depletion in MnTE-2-PyP-induced prostate cancer cell growth inhibition
title_short	The central role of NADPH depletion in MnTE-2-PyP-induced prostate cancer cell growth inhibition
title_full	The central role of NADPH depletion in MnTE-2-PyP-induced prostate cancer cell growth inhibition
title_fullStr	The central role of NADPH depletion in MnTE-2-PyP-induced prostate cancer cell growth inhibition
title_full_unstemmed	The central role of NADPH depletion in MnTE-2-PyP-induced prostate cancer cell growth inhibition
title_sort	central role of nadph depletion in mnte-2-pyp-induced prostate cancer cell growth inhibition
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/c88a430211594c2db68f4a6a08566a9f
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The central role of NADPH depletion in MnTE-2-PyP-induced prostate cancer cell growth inhibition

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