Thiostrepton degrades mutant p53 by eliciting an autophagic response in SW480 cells

Area of Science:

• Oncology
• Molecular Biology
• Cellular Biology

Background:

• Mutations in the p53 gene are a critical factor in cancer development.
• Targeting mutant p53 protein presents a promising therapeutic avenue for cancer treatment.

Purpose of the Study:

• To elucidate the mechanism by which thiostrepton induces mutant p53 degradation.
• To investigate the role of autophagy and the proteasome in thiostrepton-mediated mutant p53 destabilization.

Main Methods:

• Treatment of cancer cell lines (SW480, MiaPaCa, MDAMB231) with thiostrepton.
• Exploration of proteasome inhibition and its effect on autophagy activation.
• Utilizing cycloheximide/chloroquine to assess the role of autophagy.
• Investigating the involvement of BAG3 through gene silencing.
• Performing interactome analysis to identify associated proteins.
• Analyzing p53 localization within lysosomes.

Main Results:

• Thiostrepton treatment led to the destabilization of mutant p53 protein.
• Autophagy, not proteasome degradation, was identified as the primary mechanism for mutant p53 destabilization.
• BAG3 was confirmed as a key mediator in thiostrepton-induced mutant p53 degradation.
• Interactome analysis revealed associations between p53 and autophagy-related proteins (BAG3, p62, HSC70).
• Thiostrepton treatment resulted in the lysosomal localization of mutant p53.

Conclusions:

• Thiostrepton triggers the degradation of mutant p53 protein via an autophagy-dependent pathway.
• The BAG3-mediated autophagy pathway plays a crucial role in the destabilization of mutant p53.
• These findings support the development of thiostrepton-based therapies targeting mutant p53 in cancer.