Scholarlink

<p>Enzalutamide, as a second-generation anti-androgen agent, has been used to treat castration-resistant prostate cancer (CRPC) or metastatic castration-sensitive prostate cancer (mCSPC). However, enzalutamide resistance inevitably developed for most treated CRPC/mCSPC, and limited effective therapies are currently available for these enzalutamide-resistant prostate cancers. In this study, we utilize our established enzalutamide-resistant prostate cancer cell lines to reveal a vulnerability of these cancer cells to GPX4-targeted ferroptosis. Interestingly, the established enzalutamide-resistant prostate cancer cells are mixed populations that predominantly exhibit stem cell-like (SCL) and neuroendocrine-like (NEL) phenotypes and may reflect cellular heterogeneity during the development of enzalutamide resistance in prostate cancer. We further demonstrated that ACSL4, a long-chain fatty acid-CoA ligase, was upregulated by the JAK/STAT pathway in enzalutamide-resistant SCL/NEL cells, thereby facilitating tumor proliferation and metastasis while increasing sensitivity to ferroptosis. To antagonize the ACSL4-conferred ferroptosis risk, SCL/NEL cells upregulated GPX4 through AP-1 transcription complex to suppress ferroptosis and thus promoted the malignant progression of SCL/NEL cells. Notably, we characterized Auranofin, an anti-rheumatoid arthritis drug, as a ferroptosis inducer for these SCL/NEL cells in vitro and in vivo by targeting AP-1 and decreasing GPX4 expression, suggesting a new application for Auranofin in treating enzalutamide-resistant stem cell-like AP-1<sup>High</sup> CRPC.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Ferroptosis vulnerability of enzalutamide resistant prostate cancer conferred by ACSL4 overexpression and GPX4 antagonism

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月29日

查看全文
  • Yi Zhou,
  • Jiapeng He,
  • Haozhe Zhang,
  • Qiqi Wang,
  • Zhaojun Yu,
  • Yifan Zhang,
  • Sangsang Li,
  • Yitong Chen,
  • Weiwei Zhou,
  • Qianyu Xu,
  • Yu Yin,
  • Qiang Wei,
  • Chris Soon Heng Tan,
  • Ju Guo,
  • Bin Fu,
  • Hailiang Hu

摘要

Enzalutamide, as a second-generation anti-androgen agent, has been used to treat castration-resistant prostate cancer (CRPC) or metastatic castration-sensitive prostate cancer (mCSPC). However, enzalutamide resistance inevitably developed for most treated CRPC/mCSPC, and limited effective therapies are currently available for these enzalutamide-resistant prostate cancers. In this study, we utilize our established enzalutamide-resistant prostate cancer cell lines to reveal a vulnerability of these cancer cells to GPX4-targeted ferroptosis. Interestingly, the established enzalutamide-resistant prostate cancer cells are mixed populations that predominantly exhibit stem cell-like (SCL) and neuroendocrine-like (NEL) phenotypes and may reflect cellular heterogeneity during the development of enzalutamide resistance in prostate cancer. We further demonstrated that ACSL4, a long-chain fatty acid-CoA ligase, was upregulated by the JAK/STAT pathway in enzalutamide-resistant SCL/NEL cells, thereby facilitating tumor proliferation and metastasis while increasing sensitivity to ferroptosis. To antagonize the ACSL4-conferred ferroptosis risk, SCL/NEL cells upregulated GPX4 through AP-1 transcription complex to suppress ferroptosis and thus promoted the malignant progression of SCL/NEL cells. Notably, we characterized Auranofin, an anti-rheumatoid arthritis drug, as a ferroptosis inducer for these SCL/NEL cells in vitro and in vivo by targeting AP-1 and decreasing GPX4 expression, suggesting a new application for Auranofin in treating enzalutamide-resistant stem cell-like AP-1High CRPC.