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

Abstract

Caspase-8, a caspase protein, is involved in the regulation of multiple cell death modes and has a predominant role in cell death. Cancer-associated mutations in the protein-coding region of caspase-8 have been widely reported in several solid tumors and might lead to the loss of its apoptotic function and contribute to the pathogenesis of tumors. However, the specific function and molecular mechanisms of mutant caspase-8 in the development of esophageal squamous cell carcinoma (ESCC) remain unknown. Here, we identified caspase-8 mutants exert tumor-promoting properties in ESCC, patients with the mutants presented a worse prognosis, and caspase-8 mutants lost the suppressive effect on tumor growth in ESCC cells. In addition, we demonstrated that caspase-8 mutants gain a new function of abolishing excess reactive oxygen species (ROS) to maintain ESCC cell growth under oxidative stress. An Nrf2 inhibitor reduced the effects of caspase-8 mutants against oxidative stress. Caspase-8 mutants combined with mTOR to phosphorylate SQSTM1 at Ser349, facilitating the interaction of SQSTM1 and Keap1 and reducing the degradation of the Nrf2 protein. Therefore, our study demonstrated that caspase-8 mutants gain a new function of protecting against oxidative stress via the mTOR/SQSTM1/Keap1/Nrf2 axis in ESCC. Caspase-8 status may be a new prognostic factor for survival in ESCC patients.