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<p>Chemoresistance is a major cause of poor prognosis in colorectal cancer (CRC), and its molecular mechanisms urgently need elucidation. The cell membrane protein SNAP23, known for its role in vesicle secretion, also promotes CRC cell growth. However, its role in tumor chemotherapy remains unclear. This study reveals a novel function of SNAP23, independent of vesicle transport, mediating crosstalk between the cell membrane and mitochondria to influence the chemotherapeutic response to oxaliplatin (OXA). Mechanistically, SNAP23 arrests Trim21, causing its accumulation near the cell membrane and away from mitochondria. This reduces the ubiquitination and degradation of the mitochondrial transcription factor A (TFAM), enhancing mitochondrial oxidative metabolism and increasing oxidative phosphorylation (OXPHOS) and reactive oxygen species (ROS) production, ultimately heightening the sensitivity of cancer cells to OXA. The unique regulatory function of SNAP23 in the chemotherapeutic response of colorectal cancer may provide a potential target for chemotherapy sensitization.</p><p></p>

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SNAP23 deficiency triggers Trim21 mitochondrial translocation to suppress TFAM-mediated oxidative metabolism and drive chemoresistance in colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月22日

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  • Abudushalamu Yalikun,
  • Bingjie Guan,
  • Jiawei Pan,
  • Haonan Chen,
  • Jingfeng Cai,
  • Ziyan Zhu,
  • Runkai Zhou,
  • Bowen Xie,
  • Youdong Liu,
  • Jikun Li

摘要

Chemoresistance is a major cause of poor prognosis in colorectal cancer (CRC), and its molecular mechanisms urgently need elucidation. The cell membrane protein SNAP23, known for its role in vesicle secretion, also promotes CRC cell growth. However, its role in tumor chemotherapy remains unclear. This study reveals a novel function of SNAP23, independent of vesicle transport, mediating crosstalk between the cell membrane and mitochondria to influence the chemotherapeutic response to oxaliplatin (OXA). Mechanistically, SNAP23 arrests Trim21, causing its accumulation near the cell membrane and away from mitochondria. This reduces the ubiquitination and degradation of the mitochondrial transcription factor A (TFAM), enhancing mitochondrial oxidative metabolism and increasing oxidative phosphorylation (OXPHOS) and reactive oxygen species (ROS) production, ultimately heightening the sensitivity of cancer cells to OXA. The unique regulatory function of SNAP23 in the chemotherapeutic response of colorectal cancer may provide a potential target for chemotherapy sensitization.