Vorinostat Treatment of Gastric Cancer Cells Leads to ROS-Induced Cell Inhibition and a Complex Pattern of Molecular Alterations in Nrf2-Dependent Genes

Author:

Lorenz Leoni1,Zenz Tamara1,Oliinyk Denys234,Meier-Rosar Florian234,Jenke Robert1345,Aigner Achim134ORCID,Büch Thomas134

Affiliation:

1. Clinical Pharmacology, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Medical Faculty, Leipzig University, 04107 Leipzig, Germany

2. Functional Proteomics, Research Center Lobeda, Jena University Hospital, 07747 Jena, Germany

3. Comprehensive Cancer Center Central Germany (CCCG), 04103 Leipzig, Germany

4. Comprehensive Cancer Center Central Germany (CCCG), 07743 Jena, Germany

5. University Cancer Center Leipzig (UCCL), University Hospital Leipzig, 04103 Leipzig, Germany

Abstract

Histone deacetylase inhibitors (HDACi) show high antineoplastic potential in preclinical studies in various solid tumors, including gastric carcinoma; however, their use in clinical studies has not yet yielded convincing efficacies. Thus, further studies on cellular/molecular effects of HDACi are needed, for improving clinical efficacy and identifying suitable combination partners. Here, we investigated the role of oxidative stress in gastric cancer cells upon treatment with HDACi. A particular focus was laid on the role of the Nrf2 pathway, which can mediate resistance to cell-inhibitory effects of reactive oxidative species (ROS). Using fluorescence-based ROS sensors, oxidative stress was measured in human gastric cancer cell lines. Activation of the Nrf2 pathway was monitored in luciferase reporter assays as well as by mRNA and proteomic expression analyses of Nrf2 regulators and Nrf2-induced genes. Furthermore, the effects of ROS scavenger N-acetyl-L-cysteine (NAC) and Nrf2-knockdown on HDACi-dependent antiproliferative effects were investigated in colorimetric formazan-based and clonogenic survival assays. HDACi treatment led to increased oxidative stress levels and consequently, treatment with NAC reduced cytotoxicity of HDACi. In addition, vorinostat treatment stimulated expression of a luciferase reporter under the control of an antioxidative response element, indicating activation of the Nrf2 system. This Nrf2 activation was only partially reversible by treatment with NAC, suggesting ROS independent pathways to contribute to HDACi-promoted Nrf2 activation. In line with its cytoprotective role, Nrf2 knockdown led to a sensitization against HDACi. Accordingly, the expression of antioxidant and detoxifying Nrf2 target genes was upregulated upon HDACi treatment. In conclusion, oxidative stress induction upon HDAC inhibition contributes to the antitumor effects of HDAC inhibitors, and activation of Nrf2 represents a potentially important adaptive response of gastric cancer cells in this context.

Funder

Deutsche Forschungsgemeinschaft

Free state of Thuringia and the European Union

Publisher

MDPI AG

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