Gliotoxin from the marine fungus Aspergillus fumigatus induces apoptosis in HT1080 fibrosarcoma cells by downregulating NF-κB

Abstract

Gliotoxin has been recognized as an immunosuppressive agent for a long time. Recently, it was reported to have antitumor properties. However, the mechanisms by which it inhibits tumors remain unclear. Here, we showed that gliotoxin isolated from the marine fungus Aspergillus fumigatus inhibited proliferation and induced apoptosis in HT1080 human fibrosarcoma cells. Gliotoxin repressed phosphorylation-dependent degradation of IκB-α, an antagonist of nuclear factor kappa B (NF-κB), which is a known tumor-promoting factor. This coincided with a decrease in nuclear import of NF-κB, suggesting its signaling activity was impaired. Moreover, gliotoxin increased intracellular reactive oxygen species (ROS). Since ROS have been known to inhibit NF-κB, this may also contribute to gliotoxin’s antitumorigenic effects. These results suggest that gliotoxin suppressed the activation of NF-κB by inhibiting phosphorylation and degradation of IκB-α and by increasing ROS, which resulted in apoptosis of HT1080 cells. Cumulatively, gliotoxin is a promising candidate antagonist of NF-κB, and it should be investigated for its possible use as a selective inhibitor of human fibrosarcoma cells.