Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 192, Issue -, Pages 51-62Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2022.09.013
Keywords
Caspase-8 mutation; mTOR; ROS; Cell growth; ESCC
Funding
- National Key R & D Program of China
- National Natural Science Foundation of China
- CAMS Innovation Fund for Medical Sciences
- Sanming Project of Medicine in Shenzhen
- Guangdong Basic and Applied Basic Research Foundation
- [2021YFC2501000]
- [2020YFA0803300]
- [82030089]
- [82188102]
- [2021-I2M-1-018]
- [2021-I2M- 1-067]
- [SZSM201812062]
- [2019B030302012]
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This study identified that mutant caspase-8 exerts tumor-promoting properties and is associated with a worse prognosis in esophageal squamous cell carcinoma (ESCC). Mutant caspase-8 loses its inhibitory effect on tumor growth and gains a new function of protecting against oxidative stress via the mTOR/SQSTM1/Keap1/Nrf2 axis. Caspase-8 status may serve as a new prognostic factor for survival in ESCC patients.
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.
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