xCT (SLC7A11) expression confers intrinsic resistance to physical plasma treatment in tumor cells
Sander Bekeschus,
Sebastian Eisenmann,
Sanjeev Kumar Sagwal,
Yana Bodnar,
Juliane Moritz,
Broder Poschkamp,
Ingo Stoffels,
Steffen Emmert,
Muniswamy Madesh,
Klaus-Dieter Weltmann,
Thomas von Woedtke,
Rajesh Kumar Gandhirajan
Affiliations
Sander Bekeschus
Leibniz Institute for Plasma Science and Technology (INP Greifswald), ZIK Plasmatis, Felix-Hausdorff-Str. 2, 17489, Greifswald, Germany; Corresponding author.
Sebastian Eisenmann
Leibniz Institute for Plasma Science and Technology (INP Greifswald), ZIK Plasmatis, Felix-Hausdorff-Str. 2, 17489, Greifswald, Germany
Sanjeev Kumar Sagwal
Leibniz Institute for Plasma Science and Technology (INP Greifswald), ZIK Plasmatis, Felix-Hausdorff-Str. 2, 17489, Greifswald, Germany
Yana Bodnar
Leibniz Institute for Plasma Science and Technology (INP Greifswald), ZIK Plasmatis, Felix-Hausdorff-Str. 2, 17489, Greifswald, Germany
Juliane Moritz
Leibniz Institute for Plasma Science and Technology (INP Greifswald), ZIK Plasmatis, Felix-Hausdorff-Str. 2, 17489, Greifswald, Germany
Broder Poschkamp
Leibniz Institute for Plasma Science and Technology (INP Greifswald), ZIK Plasmatis, Felix-Hausdorff-Str. 2, 17489, Greifswald, Germany; Greifswald University Medical Center, Department of General, Visceral, Thoracic and Vascular Surgery, 17475, Greifswald, Germany
Ingo Stoffels
University Hospital Essen, Department of Dermatology, Venereology, and Allergology, University of Duisburg-Essen, 45122, Essen, Germany
Steffen Emmert
Rostock University Medical Center, Clinic for Dermatology and Venereology, Strempelstr. 13, 18057, Rostock, Germany
Muniswamy Madesh
Center for Precision Medicine, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
Klaus-Dieter Weltmann
Leibniz Institute for Plasma Science and Technology (INP Greifswald), ZIK Plasmatis, Felix-Hausdorff-Str. 2, 17489, Greifswald, Germany
Thomas von Woedtke
Leibniz Institute for Plasma Science and Technology (INP Greifswald), ZIK Plasmatis, Felix-Hausdorff-Str. 2, 17489, Greifswald, Germany; Institute for Hygiene and Environmental Medicine, Walther-Rathenau-Str. 48, 17489, Greifswald, Germany
Rajesh Kumar Gandhirajan
Leibniz Institute for Plasma Science and Technology (INP Greifswald), ZIK Plasmatis, Felix-Hausdorff-Str. 2, 17489, Greifswald, Germany; Corresponding author.
Cold physical plasma is a partially ionized gas investigated as a new anticancer tool in selectively targeting cancer cells in monotherapy or in combination with therapeutic agents. Here, we investigated the intrinsic resistance mechanisms of tumor cells towards physical plasma treatment. When analyzing the dose-response relationship to cold plasma-derived oxidants in 11 human cancer cell lines, we identified four ‘resistant’ and seven ‘sensitive’ cell lines. We observed stable intracellular glutathione levels following plasma treatment only in the ‘resistant’ cell lines indicative of altered antioxidant mechanisms. Assessment of proteins involved in GSH metabolism revealed cystine-glutamate antiporter xCT (SLC7A11) to be significantly more abundant in the ‘resistant’ cell lines as compared to ‘sensitive’ cell lines. This decisive role of xCT was confirmed by pharmacological and genetic inhibition, followed by cold physical plasma treatment. Finally, microscopy analysis of ex vivo plasma-treated human melanoma punch biopsies suggested a correlation between apoptosis and basal xCT protein abundance. Taken together, our results demonstrate that xCT holds the potential as a biomarker predicting the sensitivity of tumor cells towards plasma treatment. Keywords: Cancer, Glutathione, kINPen, Melanoma, Plasma medicine
