Enzalutamide Sensitizes Castration‐Resistant Prostate Cancer to Copper‐Mediated Cell Death

Autor: Xiang Gao, Haolin Zhao, Jiao Liu, Min Wang, Zhihong Dai, Wenjun Hao, Yanlong Wang, Xiang Wang, Min Zhang, Pixu Liu, Hailing Cheng, Zhiyu Liu
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Advanced Science, Vol 11, Iss 30, Pp n/a-n/a (2024)
Druh dokumentu: article
ISSN: 2198-3844
20240139
DOI: 10.1002/advs.202401396
Popis: Abstract Despite the initial efficacy of enzalutamide in castration‐resistant prostate cancer (CRPC), inevitable resistance remains a significant challenge. Here, the synergistic induction of copper‐dependent cell death (cuproptosis) in CRPC cells is reported by enzalutamide and copper ionophores (elesclomol/disulfiram). Mechanistically, enzalutamide treatment increases mitochondrial dependence in CRPC cells, rendering them susceptible to cuproptosis, as evidenced by specific reversal with the copper chelator tetrathiomolybdate. This susceptibility is characterized by hallmarks of cuproptosis, including lipoylated protein aggregation and iron‐sulfur cluster protein instability. Interestingly, the mitochondrial matrix reductase, FDX1, specifically correlates with elesclomol sensitivity, suggesting a potential mechanistic divergence between the two copper ionophores. Notably, this synergistic effect extends beyond in vitro models, demonstrating efficacy in 22Rv1 xenografts, mouse Pten p53 knockout organoids. Importantly, enzalutamide significantly enhances copper ionophore‐mediated cytotoxicity in enzalutamide‐resistant cells. Collectively, these findings indicate that enzalutamide and copper ionophores synergistically induce cuproptosis, offering a promising therapeutic avenue for CRPC, potentially including enzalutamide‐resistant cases.
Databáze: Directory of Open Access Journals
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