Autophagy mediates epithelial cancer chemoresistance by reducing p62/SQSTM1 accumulation

Area of Science:

• Oncology
• Cell Biology
• Molecular Medicine

Background:

• Cancer cells utilize adaptive pathways to manage stress, presenting therapeutic targets beyond oncogenes.
• Acquired chemoresistance is a significant clinical challenge, necessitating research into underlying cellular mechanisms.

Purpose of the Study:

• To investigate the role of adaptive pathways, specifically autophagy and the p62/SQSTM1 protein, in acquired chemoresistance in epithelial carcinoma cells.
• To establish an in vitro model for studying chemoresistance mechanisms.

Main Methods:

• HEp-2 epithelial cancer cells were conditioned in vitro with cisplatin, 5-fluorouracil, and docetaxel to induce triple drug resistance (TDR).
• Levels of oxidative stress, Nrf2 pathway activation, and autophagy were assessed in resistant cells.
• The role of p62/SQSTM1 in autophagy-mediated chemoresistance was evaluated through gene ablation, pharmacological inhibition, and mutant p62 expression.

Main Results:

• Triple-resistant HEp-2 cells exhibited increased oxidative stress and enhanced anti-stress responses, including Nrf2 activation and autophagy.
• Autophagy prevented the accumulation of reactive oxygen species and p62/SQSTM1, conferring chemoresistance.
• p62 ablation conferred resistance, while inhibiting autophagy restored drug sensitivity in a p62-dependent manner.
• Expression of a mutant p62 lacking critical binding domains increased chemosensitivity in resistant cells.

Conclusions:

• Autophagy-mediated clearance of p62/SQSTM1 is a key mechanism in acquired chemoresistance of epithelial cancers.
• Targeting p62 toxicity and autophagy presents a potential therapeutic strategy to overcome chemoresistance.
• The developed in vitro model serves as a valuable system for further investigation of chemoresistance.