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Background <p>The protein sequestosome 1 (p62) can enhance the antioxidant defense of tumor cells against chemotherapeutic agents by increasing nuclear factor erythroid 2-related factor 2 (<i>Nrf2</i>) expression.</p> Objective <p>We focused on exploring whether <i>p62</i> regulates resistance to 5-fluorouracil (5-Fu) in intrahepatic cholangiocarcinoma (ICC) cells by mediating Nrf2 expression.</p> Results <p>Higher levels of <i>p62</i> mRNA and its protein were observed in 5-Fu-resistant ICC samples and cell lines. Knockdown of <i>p62</i> lowered 5-Fu resistance in 5-Fu-resistant ICC cells, along with a strong inhibition of cell proliferation and a potent promotion of apoptosis in response to 5-Fu stimulation. Importantly, 5-Fu-resistant ICC cells demonstrated a remarkable Nrf2 nuclear translocation, but p62 silencing overtly repressed Nrf2 nuclear translocation under 5-Fu stimulation. Also, <i>p62</i> overexpression elevated 5-Fu resistance and Nrf2 nuclear translocation in parental ICC cells, but these changes were reversed following Nrf2 silencing.</p> Conclusion <p><i>p62</i> enables ICC cells with 5-Fu resistance by boosting Nrf2 nuclear translocation, suggesting that targeting <i>p62</i> may resensitize 5-Fu-resistant ICC cells to 5-Fu.</p>

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SQSTM1/p62 confers resistance of intrahepatic cholangiocarcinoma cells to 5-Fluorouracil by promoting Nrf2 nuclear translocation

  • 期刊论文

  • 发表日期：

    2025年1月4日

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  • Xuanming Luo,
  • Qinwen Tai,
  • Xuan Liu,
  • Xingni Zhou,
  • Wenxiang Li,
  • Houbao Liu,
  • Zhenbin Ding,
  • Miyesaier Abudureyimu

摘要

Background

The protein sequestosome 1 (p62) can enhance the antioxidant defense of tumor cells against chemotherapeutic agents by increasing nuclear factor erythroid 2-related factor 2 (Nrf2) expression.

Objective

We focused on exploring whether p62 regulates resistance to 5-fluorouracil (5-Fu) in intrahepatic cholangiocarcinoma (ICC) cells by mediating Nrf2 expression.

Results

Higher levels of p62 mRNA and its protein were observed in 5-Fu-resistant ICC samples and cell lines. Knockdown of p62 lowered 5-Fu resistance in 5-Fu-resistant ICC cells, along with a strong inhibition of cell proliferation and a potent promotion of apoptosis in response to 5-Fu stimulation. Importantly, 5-Fu-resistant ICC cells demonstrated a remarkable Nrf2 nuclear translocation, but p62 silencing overtly repressed Nrf2 nuclear translocation under 5-Fu stimulation. Also, p62 overexpression elevated 5-Fu resistance and Nrf2 nuclear translocation in parental ICC cells, but these changes were reversed following Nrf2 silencing.

Conclusion

p62 enables ICC cells with 5-Fu resistance by boosting Nrf2 nuclear translocation, suggesting that targeting p62 may resensitize 5-Fu-resistant ICC cells to 5-Fu.