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Author: Bekeschus, Sander × End date: 2024 × DDC: 570 × Publisher: Amsterdam [u.a.] : Elsevier × Subject: Cancer ×

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    Cell cycle-related genes associate with sensitivity to hydrogen peroxide-induced toxicity
    (Amsterdam [u.a.] : Elsevier, 2022) Bekeschus, Sander; Liebelt, Grit; Menz, Jonas; Singer, Debora; Wende, Kristian; Schmidt, Anke
    Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) are well-described agents in physiology and pathology. Chronic inflammation causes incessant H2O2 generation associated with disease occurrences such as diabetes, autoimmunity, and cancer. In cancer, conditioning of the tumor microenvironment, e.g., hypoxia and ROS generation, has been associated with disease outcomes and therapeutic efficacy. Many reports have investigated the roles of the action of H2O2 across many cell lines and disease models. The genes predisposing tumor cell lines to H2O2-mediated demise are less deciphered, however. To this end, we performed in-house transcriptional profiling of 35 cell lines and simultaneously investigated each cell line's H2O2 inhibitory concentration (IC25) based on metabolic activity. More than 100-fold differences were observed between the most resistant and sensitive cell lines. Correlation and gene ontology pathway analysis identified a rigid association with genes intertwined in cell cycle progression and proliferation, as such functional categories dominated the top ten significant processes. The ten most substantially correlating genes (Spearman r > 0.70 or < -0.70) were validated using qPCR, showing complete congruency with microarray analysis findings. Western blotting confirmed the correlation of cell cycle-related proteins negatively correlating with H2O2 IC25. Top genes related to ROS production or antioxidant defense were only modest in correlation (Spearman r > 0.40 or < -0.40). In conclusion, our in-house transcriptomic correlation analysis revealed a set of cell cycle-associated genes associated with a priori resistance or sensitivity to H2O2-induced cellular demise with the detailed and causative roles of individual genes remaining unclear.
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    xCT (SLC7A11) expression confers intrinsic resistance to physical plasma treatment in tumor cells
    (Amsterdam [u.a.] : Elsevier, 2020) Bekeschus, Sander; Eisenmann, Sebastian; Sagwal, Sanjeev Kumar; Bodnar, Yana; Moritz, Juliane; Poschkamp, Broder; Stoffels, Ingo; Emmert, Steffen; Madesh, Muniswamy; Weltmann, Klaus-Dieter; von Woedtke, Thomas; Gandhirajan, Rajesh Kumar
    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.