Withaferin A and Celastrol Overwhelm Proteostasis.

Area of Science:

• Natural Products Chemistry
• Molecular Pharmacology
• Cell Biology

Background:

• Withaferin A (WA) and celastrol (CEL) are bioactive plant compounds used in traditional medicine.
• Both WA and CEL exhibit anticancer properties, supported by extensive in vitro and in vivo research.

Purpose of the Study:

• To synthesize available information and elucidate the shared molecular mechanisms of action for WA and CEL.
• To investigate how these compounds induce cell death and explore their impact on cellular stress pathways.

Main Methods:

• Comparative analysis of existing studies on WA and CEL.
• Proteomic analysis to identify protein targets and modifications.
• Investigation of the unfolded protein response (UPR) activation and downstream signaling pathways.

Main Results:

• WA and CEL covalently bind to numerous proteins, inducing proteotoxic stress and partial protein unfolding.
• Both compounds activate the unfolded protein response (UPR), leading to apoptosis via the PERK/eIF-2/ATF4/CHOP pathway.
• Cellular context confers target specificity despite the compounds acting as electrophilic reactants.

Conclusions:

• WA and CEL share fundamental anticancer mechanisms involving proteotoxic stress and UPR activation.
• These natural compounds represent promising leads for anticancer drug development.
• Understanding their molecular interactions is crucial for optimizing therapeutic applications.