Suppression of NRF2/ARE by convallatoxin sensitises A549 cells to 5-FU-mediated apoptosis

Area of Science:

• Molecular biology
• Cancer research
• Pharmacology

Background:

• Nuclear factor erythroid 2-related factor 2 (NRF2) controls protective enzymes against oxidative stress.
• Elevated NRF2 levels in cancer promote tumor growth, chemoresistance, and radioresistance.
• Targeting NRF2 is a strategy to overcome cancer's resistance to therapy.

Purpose of the Study:

• To identify novel inhibitors of the NRF2/ARE pathway.
• To investigate the mechanism of NRF2 inhibition by convallatoxin.
• To evaluate convallatoxin's potential as a chemotherapeutic adjuvant.

Main Methods:

• Screening for NRF2/ARE inhibitors.
• Investigating the mechanism of NRF2 suppression (transcriptional vs. proteolysis).
• Assessing the role of GSK-3β and the Neh6 domain in NRF2 inhibition.
• Evaluating the effect of convallatoxin on A549 cell sensitivity to 5-fluorouracil.

Main Results:

• Convallatoxin was identified as a novel inhibitor of NRF2/ARE.
• Convallatoxin suppressed NRF2 protein levels via proteolysis, not transcriptional regulation.
• Convallatoxin-induced NRF2 suppression required GSK-3β activation and the Neh6 domain.
• Convallatoxin enhanced apoptosis and sensitized A549 lung cancer cells to 5-fluorouracil.

Conclusions:

• Convallatoxin effectively inhibits NRF2/ARE through proteolysis.
• Convallatoxin demonstrates potential as a chemotherapeutic adjuvant by overcoming drug resistance.
• Targeting NRF2 with convallatoxin may offer a new strategy in cancer treatment.