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Andrographolide Promotes Ferroptosis in Pancreatic Cancer via Targeting and Activating HSP90/GPX4 Ubiquitination
Asmat Ullah1, Hongyan Xing1, Xinxin Wang1
1College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China.
Abstract:
Pancreatic adenocarcinoma accounts for 90% of pancreatic cancer cases, the deadliest kind. PC patients' poor immunotherapy, chemotherapy, and other responses lead to a generally failed treatment strategy. Thus, understanding molecular processes is essential for creating novel PC therapies. The natural chemical andrographolide (ADG) from Andrographis paniculata shows anticancer properties against various cancer types. The method by which ADG fights pancreatic cancer is unknown. In PC cell lines, ADG inhibited cell proliferation and migration, caused G0/G1 phase arrest, and caused cell death due to reactive oxygen species, iron accumulation, malondialdehyde production, and glutathione (GSH) exhaustion. Ferrostatin-1 inhibited ADG-induced cell death. A molecular docking investigation demonstrated that ADG directly binds to heat shock protein 90 (HSP90). ADG suppresses HSP90 expression, and tanespimycin prevents ADG-induced cytotoxicity, showing that HSP90 is ADG's main target in activating intracellular activities. Tests using immunoprecipitation, degradation, and in vitro ubiquitination showed that the ADG-HSP90 pair targeted and broke down glutathione peroxidase 4 (GPX4), allowing it to be tagged for destruction. ADG also reduced cell development, caused apoptosis, increased reactive oxygen species and iron, synthesized malondialdehyde, depleted glutathione, and ubiquitinated and degraded GPX4. In subcutaneous in vivo tumors, ferroptosis caused by ADG inhibits tumor development. HSP90 is a new ADG target. After connecting to and complexing with HSP90, ADG targeted and deleted GPX4, triggering ferroptosis in PC. The findings strongly suggest that ADG may treat PC. ADG's pharmacokinetics and other effects must be studied in patients' clinical trials to make it a pancreatic cancer therapy option.
Insights
Andrographolide (ADG) combats pancreatic cancer by targeting heat shock protein 90 (HSP90), leading to the degradation of GPX4 and triggering ferroptosis. This natural compound shows promise for novel pancreatic cancer therapies.
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.
