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<p>The dysfunction of the sodium-iodide symporter (NIS) is a key contributor to radioiodine (RAI) treatment failure in advanced thyroid cancer. This dysfunction exists on a spectrum, ranging from intrinsically suppressed NIS expression—often driven by constitutive oncogenic signaling—to its complete loss in dedifferentiated disease. While MAPK pathway inhibitors represent a promising redifferentiation strategy, their clinical utility is constrained by variable efficacy and toxicity. This study aimed to investigate the potential of Tripterygium Glycosides (TG), a natural compound with known MAPK-inhibitory activity, to reactivate NIS function in preclinical models characterized by intrinsically low NIS expression, representing an early stage in the continuum of RAI resistance. This study utilized thyroid cancer cell lines with intrinsically low NIS expression. <i>In vitro</i>assays evaluated the effects of TG on iodide uptake, NIS expression and membrane localization, its interaction with the scaffold protein LARG, and the role of the ERK1/2 signaling pathway. In thyroid cancer mouse xenograft model, the effects of TG alone or in combination with <sup>131</sup>I on intratumoral iodine retention and tumor growth were assessed. TG treatment dose-dependently enhanced iodide uptake and increased total NIS protein levels. Mechanistically, TG inhibited the ERK1/2 signaling pathway. This inhibition promoted NIS transcription while concurrently destabilizing the NIS-LARG protein complex, synergistically facilitating the functional membrane localization of NIS. In animal studies, the combination of TG and <sup>131</sup>I significantly enhanced intratumoral iodine retention and suppressed tumor growth compared to <sup>131</sup>I monotherapy. This study demonstrates that TG can effectively restore NIS function and enhance RAI efficacy in thyroid cancer models with MAPK pathway hyperactivation and intrinsic NIS suppression. Its action is mediated through the dual regulation of NIS transcription and membrane localization following MAPK/ERK pathway inhibition. These findings provide preclinical proof-of-concept for TG as a potential redifferentiating agent targeting thyroid cancers with MAPK-driven intrinsic NIS suppression and establish a mechanistic rationale. Future studies in more advanced, dedifferentiated models (e.g., anaplastic thyroid cancer) are warranted to evaluate the broader applicability of this approach across the RAI-resistance spectrum.</p>

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Uptake in thyroid Tripterygium glycosides, enhances radioiodine cancer by promoting the expression and function of NIS

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月28日

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  • Zhangguo Ying,
  • Wangang Gong,
  • Mengmeng Shi,
  • Yujie Chen,
  • Yalan Dai

摘要

The dysfunction of the sodium-iodide symporter (NIS) is a key contributor to radioiodine (RAI) treatment failure in advanced thyroid cancer. This dysfunction exists on a spectrum, ranging from intrinsically suppressed NIS expression—often driven by constitutive oncogenic signaling—to its complete loss in dedifferentiated disease. While MAPK pathway inhibitors represent a promising redifferentiation strategy, their clinical utility is constrained by variable efficacy and toxicity. This study aimed to investigate the potential of Tripterygium Glycosides (TG), a natural compound with known MAPK-inhibitory activity, to reactivate NIS function in preclinical models characterized by intrinsically low NIS expression, representing an early stage in the continuum of RAI resistance. This study utilized thyroid cancer cell lines with intrinsically low NIS expression. In vitroassays evaluated the effects of TG on iodide uptake, NIS expression and membrane localization, its interaction with the scaffold protein LARG, and the role of the ERK1/2 signaling pathway. In thyroid cancer mouse xenograft model, the effects of TG alone or in combination with 131I on intratumoral iodine retention and tumor growth were assessed. TG treatment dose-dependently enhanced iodide uptake and increased total NIS protein levels. Mechanistically, TG inhibited the ERK1/2 signaling pathway. This inhibition promoted NIS transcription while concurrently destabilizing the NIS-LARG protein complex, synergistically facilitating the functional membrane localization of NIS. In animal studies, the combination of TG and 131I significantly enhanced intratumoral iodine retention and suppressed tumor growth compared to 131I monotherapy. This study demonstrates that TG can effectively restore NIS function and enhance RAI efficacy in thyroid cancer models with MAPK pathway hyperactivation and intrinsic NIS suppression. Its action is mediated through the dual regulation of NIS transcription and membrane localization following MAPK/ERK pathway inhibition. These findings provide preclinical proof-of-concept for TG as a potential redifferentiating agent targeting thyroid cancers with MAPK-driven intrinsic NIS suppression and establish a mechanistic rationale. Future studies in more advanced, dedifferentiated models (e.g., anaplastic thyroid cancer) are warranted to evaluate the broader applicability of this approach across the RAI-resistance spectrum.