1. Non-apoptotic function of caspase-8 confers prostate cancer enzalutamide resistance via NF-κB activation.
- Author
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Xia J, Zhang J, Wang L, Liu H, Wang J, Liu J, Liu Z, Zhu Y, Xu Y, Yang W, and Yu Y
- Subjects
- CASP8 and FADD-Like Apoptosis Regulating Protein metabolism, Cell Line, Tumor, Cell Survival drug effects, Disease Progression, Gene Expression Regulation, Neoplastic drug effects, Humans, Male, Models, Biological, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Transcriptome genetics, Up-Regulation drug effects, Apoptosis, Benzamides pharmacology, Caspase 8 metabolism, Drug Resistance, Neoplasm drug effects, NF-kappa B metabolism, Nitriles pharmacology, Phenylthiohydantoin pharmacology, Prostatic Neoplasms enzymology
- Abstract
Caspase-8 is a unique member of caspases with a dual role in cell death and survival. Caspase-8 expression is often lost in some tumors, but increased in others, indicating a potential pro-survival function in cancer. By analyzing transcriptome of enzalutamide-resistant prostate cancer cells, we found that resistance was conferred by a mild caspase-8 upregulation that in turn led to NF-κB activation and the subsequent upregulation of the downstream IL-8. Mechanistically, we found that the pro-survival and enzalutamide-resistance-promoting features of caspase-8 were independent of its proteolytic activity, using a catalytically-inactive caspase-8 mutant. We further demonstrated that caspase-8 pro-apoptotic function was inhibited via cFLIP binding. Moreover, high caspase-8 expression was correlated with a worse prognosis in prostate cancer patients. Collectively, our work demonstrates that enzalutamide-resistance is mediated by caspase-8 upregulation and the consequent increase in NF-κB/IL-8 mediated survival signaling, highlighting caspase-8 and NF-κB as potential therapeutic targets to overcome enzalutamide-resistance in CRPC., (© 2021. The Author(s).)
- Published
- 2021
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