p62/SQSTM1-induced caspase-8 aggresomes are essential for ionizing radiation-mediated apoptosis

Area of Science:

• Cell Biology
• Oncology
• Cancer Research

Background:

• The autophagy-lysosome pathway and apoptosis are critical for cell fate.
• p62/SQSTM1/Sequestosome-1 is a key adaptor protein linking autophagy and apoptosis.
• Head and neck squamous cell carcinoma (HNSCC) has distinct subtypes based on HPV status.

Purpose of the Study:

• To investigate the role of p62-mediated apoptosis in HNSCC radioresistance.
• To explore the differential response to radiation in HPV(-) and HPV(+) HNSCC.
• To identify therapeutic strategies targeting p62 in radioresistant HNSCC.

Main Methods:

• Analysis of autophagic flux and apoptosis in HPV(-) and HPV(+) HNSCC.
• Correlation of radioresistance and tumor progression with autophagic activity and p62 levels.
• Pharmacological activation of the p62-ZZ domain using small molecule ligands.

Main Results:

• HPV(-) HNSCC exhibits increased autophagic flux and defective apoptosis, correlating with radioresistance and p62 levels.
• HPV(+) HNSCC shows impaired autophagic flux and readily undergoes apoptosis upon radiation.
• Small molecule ligands targeting the p62-ZZ domain sensitized radioresistant HPV(-) HNSCC to ionizing radiation.

Conclusions:

• p62 self-polymerization and sequestration of ubiquitinated caspase-8 into aggresome-like structures are essential for radiation-induced apoptosis.
• Harnessing p62-dependent mechanisms offers a novel therapeutic approach for radioresistant HNSCC.
• Targeting p62 may overcome radioresistance in HPV(-) HNSCC.