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Purpose <p>Glioblastoma (GBM) is an aggressive primary malignant brain tumor in adults with a median patient survival of 12–18 months post-diagnosis, and no effective treatments, to date. The PI3K/Akt and Wnt/β-catenin signaling pathways promote GBM cell growth, survival, invasiveness and therapeutic resistance. We hypothesize that inhibiting Akt and β-catenin, which are central regulatory proteins of the PI3K/Akt and Wnt/β-catenin pathway, will suppress GBM growth and progression.</p> Methods <p>Mouse glioma cells (CT-2A) and human patient–derived glioma stem cells (N08-30) were treated with pan-Akt inhibitor, MK-2206, or β-catenin inhibitor, iCRT3, to evaluate effects on cell viability, apoptosis, β-catenin transcriptional activity, and Wnt gene and protein expression, in vitro. Luciferase-expressing CT-2A cells were inoculated intracranially in immunocompetent C57BL/6J mice to assess the impact of MK-2206 treatment on tumor progression using bioluminescence imaging and immunohistochemistry.</p> Results <p>In vitro studies demonstrate that MK-2206, a pan-Akt inhibitor, effectively reduced cell viability, induced apoptosis, and inhibited β-catenin activity; consistently outperforming iCRT3, a β-catenin-TCF interaction inhibitor, in CT-2A mouse glioma cells, and N08-30 human glioma stem cells. MK-2206 significantly suppressed tumor growth in vivo, and reduced expression of phosphorylated Akt and GSK-3β in tumor tissues, confirming disruption of the Akt and Wnt/β-catenin signaling axis.</p> Conclusion <p>In summary, MK-2206 outperformed iCRT3 efficacy in vitro, and suppressed GBM progression, in vivo. These findings suggest that Akt inhibition via MK-2206 may offer a promising therapeutic strategy for treating GBM, characterized by dysregulation of PI3K/Akt or Wnt/β-catenin pathways.</p>

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Disrupting Akt-Wnt/β-catenin signaling suppresses glioblastoma stem cell growth and tumor progression in immunocompetent mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月14日

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  • Md Marzan Sarkar,
  • Nathan Gonsalves,
  • Amin Davarzani,
  • Emma Mitchell,
  • Amar M. Singh,
  • Lohitash Karumbaiah,
  • Steven L. Stice

摘要

Purpose

Glioblastoma (GBM) is an aggressive primary malignant brain tumor in adults with a median patient survival of 12–18 months post-diagnosis, and no effective treatments, to date. The PI3K/Akt and Wnt/β-catenin signaling pathways promote GBM cell growth, survival, invasiveness and therapeutic resistance. We hypothesize that inhibiting Akt and β-catenin, which are central regulatory proteins of the PI3K/Akt and Wnt/β-catenin pathway, will suppress GBM growth and progression.

Methods

Mouse glioma cells (CT-2A) and human patient–derived glioma stem cells (N08-30) were treated with pan-Akt inhibitor, MK-2206, or β-catenin inhibitor, iCRT3, to evaluate effects on cell viability, apoptosis, β-catenin transcriptional activity, and Wnt gene and protein expression, in vitro. Luciferase-expressing CT-2A cells were inoculated intracranially in immunocompetent C57BL/6J mice to assess the impact of MK-2206 treatment on tumor progression using bioluminescence imaging and immunohistochemistry.

Results

In vitro studies demonstrate that MK-2206, a pan-Akt inhibitor, effectively reduced cell viability, induced apoptosis, and inhibited β-catenin activity; consistently outperforming iCRT3, a β-catenin-TCF interaction inhibitor, in CT-2A mouse glioma cells, and N08-30 human glioma stem cells. MK-2206 significantly suppressed tumor growth in vivo, and reduced expression of phosphorylated Akt and GSK-3β in tumor tissues, confirming disruption of the Akt and Wnt/β-catenin signaling axis.

Conclusion

In summary, MK-2206 outperformed iCRT3 efficacy in vitro, and suppressed GBM progression, in vivo. These findings suggest that Akt inhibition via MK-2206 may offer a promising therapeutic strategy for treating GBM, characterized by dysregulation of PI3K/Akt or Wnt/β-catenin pathways.