Thiostrepton induces apoptotic cell death at the level of BCL-2/CED-9 in C. elegans.

Thiostrepton, a thiopeptide antibiotic, has been attracting increasing attention for its anti-proliferative and anti-cancer properties in various tested cell culture models. Extensive in vitro analysis has been conducted to understand its anti-cancer effect across multiple cancer types and cell lines, with numerous reports indicating that thiostrepton can inhibit cancer cell proliferation and tumor growth and induce apoptosis in vitro. On the other hand, the in vivo anti-tumor effect of thiostrepton remains elusive. In this study, we aimed to genetically and physiologically characterize the effects of thiostrepton on apoptosis induction in vivo using C. elegans. Our data demonstrate that thiostrepton induces apoptosis in C. elegans, and this apoptotic induction is independent of the genomic instability and is not related to p53 activity. Rather, the apoptotic cell death mediated by thiostrepton treatment occurs at the level of the BCL-2/CED-9 protein at the core apoptotic machinery. Furthermore, we have unlinked the high ROS (reactive oxygen species) induction reported in earlier in vitro studies from apoptosis induction upon thiostrepton treatment in C. elegans. Overall, our genetic data indicate that apoptosis induction mediated by thiostrepton occurs at the level of the core apoptotic machinery.