| Popis: |
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 underlying liver disease and a shortage of organ donors. Especially after LR, we are dealing with high recurrence rates, 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 at investigating the effect of tigecycline on HCC cell lines and its mechanisms of action. Methods: Huh7, HepG2 cells, 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 and RT-PCR. 2',7'-dichlorofluorescein diacetate (DCFH-DA) was utilized to measure reactive oxygen species (ROS) generation upon tigecycline treatment. FACS was used to detect alterations in the cell cycle and changes in mitochondrial function were detected via seahorse analysis. Results: Tigecycline treatment resulted in a significant reduction of mitochondrial function, which preceded the observed loss of HCC cell viability. The sensitivity of HCC cells to tigecycline treatment was higher than that of immortalized non-cancerous THLE-2 hepatocytes, indicating a selective antitumoral efficacy. Tigecycline inhibited both migration and invasion. Bioinformatic analysis identified RAC1 as a possible target for tigecycline and the expression of this molecule was increased in both HCC as a result of tigecycline treatment. Tigecycline also caused decreased ROS production and an S-phase cell cycle arrest. Conclusion: Our study provides evidence for the antiproliferative effect of tigecycline in HCC. We show for the first time that this effect, likely to be mediated by reduced OXPHOS, is associated with increased expression of RAC1. The selective effect of tigecycline on HCC cells versus normal hepatocytes represents the rationale for the possible use of this agent in cancer treatment. |
