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<p>Isocitrate dehydrogenase 1 (IDH1) mutations are prevalent in various cancers and have significant implications for tumor biology. It is known that cancer cells with IDH1 mutations, particularly R132C or R132H, exhibit decreased production of nicotinamide adenine dinucleotide phosphate and thus impaired glutathione synthesis. This study investigated the roles of IDH1 mutations in the regulation of nuclear factor erythroid-2-related factor 2 (Nrf2)-mediated signaling pathways in fibrosarcoma HT1080 cells harboring the IDH1 R132C mutation. Knockdown of IDH1 using siRNA in HT1080 cells inhibited Nrf2 stabilization and reduced the expression of antioxidant genes, thereby providing favorable conditions for cancer progression. In addition, inhibition of IDH1 decreased reactive oxygen species (ROS) production and impaired cell migration, highlighting its role in promoting malignant behavior such as colony-forming ability. Small molecule inhibitors targeting the IDH1 R132 mutation suppressed cell migration and colony formation in HT1080 cells. Moreover, we observed that IDH and Nrf2 contribute to immune evasion by modulating the expression of programmed death-ligand 1 (PD-L1) in HT1080 cells. Altogether, our findings provide valuable insights for the development of therapeutic approaches for IDH1-mutant cancers. We suggest targeting the IDH1-Nrf2 axis as a strategy to regulate the immune response and inhibit cell migration in fibrosarcoma.</p>

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Targeting IDH1 mutation-driven Nrf2 signaling to suppress malignant behavior in fibrosarcoma cells

  • 期刊论文

  • 发表日期：

    2025年2月20日

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  • Seoyeon Park,
  • Kyung-Soo Chun,
  • Do-Hee Kim

摘要

Isocitrate dehydrogenase 1 (IDH1) mutations are prevalent in various cancers and have significant implications for tumor biology. It is known that cancer cells with IDH1 mutations, particularly R132C or R132H, exhibit decreased production of nicotinamide adenine dinucleotide phosphate and thus impaired glutathione synthesis. This study investigated the roles of IDH1 mutations in the regulation of nuclear factor erythroid-2-related factor 2 (Nrf2)-mediated signaling pathways in fibrosarcoma HT1080 cells harboring the IDH1 R132C mutation. Knockdown of IDH1 using siRNA in HT1080 cells inhibited Nrf2 stabilization and reduced the expression of antioxidant genes, thereby providing favorable conditions for cancer progression. In addition, inhibition of IDH1 decreased reactive oxygen species (ROS) production and impaired cell migration, highlighting its role in promoting malignant behavior such as colony-forming ability. Small molecule inhibitors targeting the IDH1 R132 mutation suppressed cell migration and colony formation in HT1080 cells. Moreover, we observed that IDH and Nrf2 contribute to immune evasion by modulating the expression of programmed death-ligand 1 (PD-L1) in HT1080 cells. Altogether, our findings provide valuable insights for the development of therapeutic approaches for IDH1-mutant cancers. We suggest targeting the IDH1-Nrf2 axis as a strategy to regulate the immune response and inhibit cell migration in fibrosarcoma.