Non-apoptotic Function of Caspase-8 Confers Prostate Cancer Enzalutamide Resistance Via NF-κB Activation

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2021 Sep 5

PMID 34482382

Citations 8

Authors

Jia Xia

Jiahui Zhang

Liangzhe Wang

Hailong Liu

Jie Wang

Junyan Liu

Zhaoqian Liu

Yingjian Zhu

Yingjie Xu

Wen Yang

Yongjiang Yu

Affiliations

Soon will be listed here.

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.

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