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<p>Chemotherapy resistance remains a major challenge in colorectal cancer (CRC) treatment, yet the underlying mechanisms remain incompletely understood. Here, we demonstrate that CDC-like kinase 2 (CLK2) expression is significantly upregulated in CRC tissues and correlates with poor chemotherapeutic outcomes. CLK2 shows distinct nuclear-mitochondrial localization in chemoresistant cells compared to predominantly nuclear localization in parental cells. Mechanistically, mitochondrial CLK2 maintains enhanced oxidative phosphorylation and suppresses ferroptosis in resistant cells. CLK2 depletion or pharmacological inhibition sensitizes resistant cells to 5-fluorouracil and oxaliplatin treatment through disruption of mitochondrial function and enhanced ferroptosis sensitivity. Moreover, combined targeting of CLK2 and mitochondrial function shows synergistic effects in overcoming chemoresistance. Our findings reveal a previously unrecognized role of mitochondrial CLK2 in promoting chemotherapy resistance through regulation of mitochondrial metabolism and ferroptosis, suggesting potential therapeutic strategies for drug-resistant colorectal cancer.</p>

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Mitochondrial CLK2 promotes chemotherapy resistance in colorectal Cancer by regulating oxidative phosphorylation and ferroptosis

  • 期刊论文

  • 发表日期：

    2025年7月23日

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  • Xingchun Xiao,
  • Qiling Lin,
  • Wentai Shi

摘要

Chemotherapy resistance remains a major challenge in colorectal cancer (CRC) treatment, yet the underlying mechanisms remain incompletely understood. Here, we demonstrate that CDC-like kinase 2 (CLK2) expression is significantly upregulated in CRC tissues and correlates with poor chemotherapeutic outcomes. CLK2 shows distinct nuclear-mitochondrial localization in chemoresistant cells compared to predominantly nuclear localization in parental cells. Mechanistically, mitochondrial CLK2 maintains enhanced oxidative phosphorylation and suppresses ferroptosis in resistant cells. CLK2 depletion or pharmacological inhibition sensitizes resistant cells to 5-fluorouracil and oxaliplatin treatment through disruption of mitochondrial function and enhanced ferroptosis sensitivity. Moreover, combined targeting of CLK2 and mitochondrial function shows synergistic effects in overcoming chemoresistance. Our findings reveal a previously unrecognized role of mitochondrial CLK2 in promoting chemotherapy resistance through regulation of mitochondrial metabolism and ferroptosis, suggesting potential therapeutic strategies for drug-resistant colorectal cancer.