Andrographolide Promotes Ferroptosis in Pancreatic Cancer via Targeting and Activating HSP90/GPX4 Ubiquitination

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Pancreatic cancer, particularly adenocarcinoma, has poor treatment outcomes due to resistance to conventional therapies.
• Novel therapeutic strategies are crucial for improving pancreatic cancer patient survival.
• Andrographolide (ADG), a natural compound, exhibits anticancer properties, but its mechanism in pancreatic cancer is unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms by which andrographolide (ADG) exerts its anticancer effects in pancreatic cancer.
• To identify the specific molecular targets of ADG in pancreatic cancer cells.
• To evaluate the therapeutic potential of ADG in preclinical models of pancreatic cancer.

Main Methods:

• Cell proliferation, migration, and apoptosis assays were performed in pancreatic cancer cell lines treated with ADG.
• Reactive oxygen species (ROS), iron levels, malondialdehyde, and glutathione (GSH) were measured.
• Molecular docking was used to predict ADG binding targets.
• Immunoprecipitation, degradation assays, and in vitro ubiquitination were employed to study protein interactions and degradation.
• ADG's efficacy was assessed in subcutaneous in vivo tumor models.

Main Results:

• ADG inhibited pancreatic cancer cell proliferation and migration, induced G0/G1 phase arrest, and promoted cell death.
• ADG-induced cell death involved ROS generation, iron accumulation, malondialdehyde production, and GSH depletion, consistent with ferroptosis.
• Molecular docking and experimental validation identified heat shock protein 90 (HSP90) as a direct target of ADG.
• ADG, through HSP90, led to the ubiquitination and degradation of glutathione peroxidase 4 (GPX4).
• ADG suppressed tumor growth in vivo by inducing ferroptosis.

Conclusions:

• ADG effectively inhibits pancreatic cancer progression by targeting HSP90, leading to GPX4 degradation and ferroptosis induction.
• HSP90 is identified as a novel molecular target for ADG in pancreatic cancer.
• ADG demonstrates significant therapeutic potential as a novel treatment option for pancreatic cancer, warranting further clinical investigation.