Caspase-8 mutants activate Nrf2 via phosphorylating SQSTM1 to protect against oxidative stress in esophageal squamous cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Cell Death Research

Background:

• Caspase-8 is crucial for cell death regulation.
• Cancer-associated caspase-8 mutations are common in solid tumors, potentially affecting its apoptotic function.
• The role of mutant caspase-8 in esophageal squamous cell carcinoma (ESCC) pathogenesis is unclear.

Purpose of the Study:

• To investigate the function and molecular mechanisms of mutant caspase-8 in ESCC.
• To determine if caspase-8 mutations impact patient prognosis in ESCC.
• To elucidate how mutant caspase-8 influences tumor growth and survival under oxidative stress.

Main Methods:

• Identification and characterization of caspase-8 mutants in ESCC.
• Analysis of patient prognosis based on caspase-8 mutation status.
• In vitro studies to assess the effect of caspase-8 mutants on cell growth, reactive oxygen species (ROS) levels, and the Nrf2 pathway.
• Investigation of the interaction between caspase-8 mutants, mTOR, SQSTM1, Keap1, and Nrf2.

Main Results:

• Caspase-8 mutants exhibit tumor-promoting properties in ESCC and are associated with worse patient prognosis.
• Mutant caspase-8 loses its tumor-suppressive effect and gains a function in protecting ESCC cells from oxidative stress.
• Caspase-8 mutants activate the Nrf2 pathway by stabilizing Nrf2 protein via the mTOR/SQSTM1/Keap1 axis, thereby reducing ROS levels.
• Inhibition of Nrf2 diminishes the protective effects of caspase-8 mutants against oxidative stress.

Conclusions:

• Mutant caspase-8 gains a novel function in protecting ESCC cells against oxidative stress through the mTOR/SQSTM1/Keap1/Nrf2 signaling pathway.
• Caspase-8 mutation status may serve as a novel prognostic biomarker for survival in ESCC patients.