Mutant p53, Stabilized by Its Interplay with HSP90, Activates a Positive Feed-Back Loop Between NRF2 and p62 that...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Pancreatic cancer exhibits aggressive behavior and poor response to chemotherapy.
• Apigenin, a natural flavonoid, possesses anti-inflammatory and anticancer properties.
• Understanding resistance mechanisms is crucial for improving pancreatic cancer treatment.

Purpose of the Study:

• To investigate the cytotoxic effects of Apigenin on pancreatic cancer cell lines (Panc1 and PaCa44).
• To elucidate the molecular mechanisms underlying differential sensitivity to Apigenin.
• To identify potential therapeutic targets for overcoming chemo-resistance.

Main Methods:

• Cytotoxicity assays on Panc1 and PaCa44 cell lines treated with Apigenin.
• Measurement of intracellular reactive oxygen species (ROS) levels.
• Analysis of mutant p53 (mutp53), HSP90, mTORC1, NRF2, and p62 expression.
• Investigation of the feedback loop between NRF2 and p62.

Main Results:

• Apigenin demonstrated greater cytotoxicity against Panc1 cells compared to PaCa44 cells.
• Higher Apigenin cytotoxicity correlated with increased ROS, reduced mutp53 and HSP90, and mTORC1 inhibition.
• Mutp53 stabilization by HSP90 activates a positive feedback loop involving NRF2 and p62, enhancing antioxidant response and reducing Apigenin's effect.
• A feedback loop involving NRF2 and p62 was identified, which upregulates the antioxidant response.

Conclusions:

• Differential sensitivity of pancreatic cancer cells to Apigenin is linked to ROS levels, mutp53/HSP90 expression, and mTORC1 activity.
• The interplay between HSP90, mutp53, NRF2, and p62 contributes to Apigenin resistance.
• Targeting the mTOR-HSP90-mutp53-p62-NRF2 axis presents a potential strategy to enhance pancreatic cancer chemo-resistance.