Mitochondrial dysfunction generates aggregates that resist lysosomal degradation in human breast cancer cells

Area of Science:

• Biochemistry
• Cell Biology
• Oncology

Background:

• Disrupting protein homeostasis is a cancer therapy strategy.
• Autophagy inhibition is explored to overcome chemotherapy resistance by targeting lysosomal pH.
• Sensitive methods to monitor autophagy in patients are crucial for clinical trial optimization.

Purpose of the Study:

• To identify novel biomarkers for monitoring autophagy and lysosomal degradation.
• To investigate the role of protein aggregates and autophagy receptors in cancer cells.
• To validate potential monitoring methods in primary human tumor samples.

Main Methods:

• Utilized mitochondrial damage models in breast cancer cells and rat tumors.
• Analyzed p53-positive protein aggregates within autolysosomes.
• Investigated the association and function of autophagy receptors TAX1BP1 and NDP52 using knockdown experiments.

Main Results:

• Mitochondrial-damaged cells and tumors accumulated p53-positive protein aggregates resistant to lysosomal degradation.
• These aggregates localized to active autolysosomes degrading autophagosomes and autophagy receptors.
• NDP52 knockdown increased protein aggregates; TAX1BP1 knockdown enhanced aggregation, suppressed autophagy, and induced cell death.

Conclusions:

• Protein aggregates and autophagy receptors TAX1BP1 and NDP52 are potential endpoints for evaluating autophagy and lysosomal degradation.
• Quantifying these markers can aid in monitoring autophagy during drug development and clinical studies.
• This study provides new insights into autophagy modulation in cancer therapy.