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Thiostrepton induces apoptotic cell death at the level of BCL-2/CED-9 in C. elegans
Alanoud Al-Kaabi1,2, Tayyiba Akbar Ali1, Mahmoud Izadi1
1Division of Genomics and Translational Medicine, College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, 34110, Qatar.
Abstract:
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.
Insights
Thiostrepton, an antibiotic, triggers apoptosis in C. elegans by targeting the core apoptotic machinery. This cancer-fighting effect is independent of genomic instability and reactive oxygen species.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Thiostrepton, a thiopeptide antibiotic, shows anti-cancer properties in vitro.
- Its in vivo anti-tumor effects and mechanisms remain largely uncharacterized.
Purpose of the Study:
- To investigate the in vivo effects of thiostrepton on apoptosis induction.
- To elucidate the molecular mechanisms underlying thiostrepton-induced apoptosis in a whole organism model.
Main Methods:
- Utilized Caenorhabditis elegans (C. elegans) as a model organism for in vivo studies.
- Employed genetic and physiological characterization to analyze apoptosis induction.
- Investigated the role of genomic instability, p53, and reactive oxygen species (ROS).
Main Results:
- Thiostrepton effectively induces apoptosis in C. elegans.
- Apoptosis induction is independent of genomic instability and p53 activity.
- The mechanism involves direct action on the core apoptotic machinery, specifically at the BCL-2/CED-9 protein level.
- High ROS induction, previously linked to thiostrepton in vitro, is uncoupled from apoptosis in vivo.
Conclusions:
- Thiostrepton induces apoptosis in vivo via a mechanism distinct from genomic instability and ROS.
- The primary target appears to be the core apoptotic machinery, highlighting a conserved pathway.
- C. elegans serves as a valuable model for dissecting the in vivo anti-cancer mechanisms of compounds like thiostrepton.
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