Tigecycline causes loss of cell viability mediated by mitochondrial OXPHOS and RAC1 in hepatocellular carcinoma cells

作者：Dominik Thomas Koch, Haochen Yu, Iris Beirith, Malte Schirren, Moritz Drefs, Yunfei Liu, Mathilda Knoblauch, Dionysios Koliogiannis, Weiwei Sheng, Enrico Narciso De Toni, Alexandr V. Bazhin, Bernhard Willibald Renz, Markus Otto Guba, Jens Werner, Matthias Ilmer · 发表于：Journal of Translational Medicine · 年份：2023 · DOI：10.1186/s12967-023-04615-4 · 被引用次数：21 · 研究领域：Cancer Research and Treatments、Hepatocellular Carcinoma Treatment and Prognosis、Immune cells in cancer

BACKGROUND: Despite recent advances in locoregional, systemic, and novel checkpoint inhibitor treatment, hepatocellular carcinoma (HCC) is still associated with poor prognosis. The feasibility of potentially curative liver resection (LR) and transplantation (LT) is limited by the underlying liver disease and a shortage of organ donors. Especially after LR, high recurrence rates present a problem and circulating tumor cells are a major cause of extrahepatic recurrence. Tigecycline, a commonly used glycylcycline antibiotic, has been shown to have antitumorigenic effects and could be used as a perioperative and adjuvant therapeutic strategy to target circulating tumor cells. We aimed to investigate the effect of tigecycline on HCC cell lines and its mechanisms of action. METHODS: Huh7, HepG2, Hep3B, and immortalized hepatocytes underwent incubation with clinically relevant tigecycline concentrations, and the influence on proliferation, migration, and invasion was assessed in two- and three-dimensional in vitro assays, respectively. Bioinformatic analysis was used to identify specific targets of tigecycline. The expression of RAC1 was detected using western blot, RT-PCR and RNA sequencing. ELISA and flow cytometry were utilized to measure reactive oxygen species (ROS) generation upon tigecycline treatment and flow cytometry to detect alterations in cell cycle. Changes in mitochondrial function were detected via seahorse analysis. RNA sequencing was performed to examine involved p...