Scholarlink

<p>Cisplatin resistance is a major obstacle in the treatment of esophageal squamous cell carcinoma (ESCC). To address this challenge, we screened a U.S. Food and Drug Administration (FDA)-approved drug library and identified fingolimod, an immunomodulatory agent, as a potent inhibitor of cisplatin-resistant ESCC cells. Fingolimod is likely to directly binds to Glu266 of the nuclear pore complex protein NUP54, promoting its proteasomal degradation. This disrupts the NUP54-NUP58-NUP62 central channel, impairing the nuclear import of the key DNA repair protein SPIDR. Consequently, fingolimod treatment inhibits the recruitment of the SPIDR-RAD51-DMC1 complex by chromatin, causing defective homologous recombination repair, accumulation of DNA damage, and ultimately, the reversal of cisplatin resistance. In addition, fingolimod restored the sensitivity of cisplatin to ESCC treatment in both patient-derived xenograft and organoid models. Our study unveils a novel mechanism by which fingolimod targets the nuclear pore complex to suppress DNA repair, providing a compelling rationale for repurposing fingolimod as a combination therapy to overcome cisplatin resistance in ESCC.</p> Graphical Abstract <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

Fingolimod overcomes cisplatin resistance in esophageal squamous cell carcinoma by targeting NUP54 to disrupt homologous recombination repair

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月1日

查看全文
  • Duo Cao,
  • Jin Liu,
  • Guoliang Chen,
  • Tianqi Xu,
  • Xiangru Zhou,
  • Junpeng Xu,
  • Pusong Zhao,
  • Peng Wang,
  • Xinya Yang,
  • Luis A. J. Mur,
  • Ligang Chen,
  • Zhenliang Sun,
  • Qingge Jia,
  • Mingyang Li

摘要

Cisplatin resistance is a major obstacle in the treatment of esophageal squamous cell carcinoma (ESCC). To address this challenge, we screened a U.S. Food and Drug Administration (FDA)-approved drug library and identified fingolimod, an immunomodulatory agent, as a potent inhibitor of cisplatin-resistant ESCC cells. Fingolimod is likely to directly binds to Glu266 of the nuclear pore complex protein NUP54, promoting its proteasomal degradation. This disrupts the NUP54-NUP58-NUP62 central channel, impairing the nuclear import of the key DNA repair protein SPIDR. Consequently, fingolimod treatment inhibits the recruitment of the SPIDR-RAD51-DMC1 complex by chromatin, causing defective homologous recombination repair, accumulation of DNA damage, and ultimately, the reversal of cisplatin resistance. In addition, fingolimod restored the sensitivity of cisplatin to ESCC treatment in both patient-derived xenograft and organoid models. Our study unveils a novel mechanism by which fingolimod targets the nuclear pore complex to suppress DNA repair, providing a compelling rationale for repurposing fingolimod as a combination therapy to overcome cisplatin resistance in ESCC.

Graphical Abstract