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Background <p>Wnt/β-catenin signaling drives many cancers; however, current inhibition strategies have limitations. Direct β-catenin inhibitors that block nuclear translocation represent an alternative therapeutic approach. We used colorectal cancer (CRC) as a study model, over 90% of the CRC cases harbor mutations in this pathway. Here, we aim to explore the potential of 15,16-dihydrotanshinone-I (DHTS) as a β-catenin inhibitor in cancer.</p> Methods <p>Molecular docking, biolayer interferometry assay and cellular thermal shift assay were used to examine the binding between DHTS and β-catenin. Site-directed mutagenesis, in vitro and in vivo studies were used to examine the anti-CRC effects of DHTS following its binding to β-catenin.</p> Results <p>We demonstrate, for the first time, that DHTS significantly reduces nuclear β-catenin levels and transcriptional activity in CRC without affecting β-catenin protein stability or conformation. DHTS binds to β-catenin at Ser411. A point mutation at Ser411 disrupts this binding and abolishes the ability of DHTS to suppress nuclear β-catenin, indicating that Ser411 binding is critical for blocking β-catenin nuclear translocation. Furthermore, we identify CD36, a transmembrane fatty acid translocase, as a downstream β-catenin target. DHTS reduces CD36 expression and cellular ATP levels in CRC cells; the reductions are reversed by β-catenin overexpression or stabilization. In CRC-bearing mouse model, DHTS-loaded PLGA-PEG nanoparticles significantly reduce nuclear β-catenin and CD36 expressions in tumors and inhibit tumor growth, consistent with the in vitro findings.</p> Conclusions <p>Our study not only reveals the importance of Ser411 in β-catenin function but also paves the path for developing DHTS as a β-catenin inhibitor for CRC therapy.</p>

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15,16-Dihydrotanshinone I, a novel β-catenin-targeting inhibitor that inhibits its nuclear translocation and reduces downstream CD36 expression in cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月21日

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  • Minting Chen,
  • Baisen Chen,
  • Qianyi He,
  • Shilin Xiao,
  • Baoting Li,
  • Yun Ye,
  • Hongjie Zhang,
  • Hoi Leong Xavier Wong,
  • Ying Ji,
  • Tao Su,
  • Hiu Yee Kwan

摘要

Background

Wnt/β-catenin signaling drives many cancers; however, current inhibition strategies have limitations. Direct β-catenin inhibitors that block nuclear translocation represent an alternative therapeutic approach. We used colorectal cancer (CRC) as a study model, over 90% of the CRC cases harbor mutations in this pathway. Here, we aim to explore the potential of 15,16-dihydrotanshinone-I (DHTS) as a β-catenin inhibitor in cancer.

Methods

Molecular docking, biolayer interferometry assay and cellular thermal shift assay were used to examine the binding between DHTS and β-catenin. Site-directed mutagenesis, in vitro and in vivo studies were used to examine the anti-CRC effects of DHTS following its binding to β-catenin.

Results

We demonstrate, for the first time, that DHTS significantly reduces nuclear β-catenin levels and transcriptional activity in CRC without affecting β-catenin protein stability or conformation. DHTS binds to β-catenin at Ser411. A point mutation at Ser411 disrupts this binding and abolishes the ability of DHTS to suppress nuclear β-catenin, indicating that Ser411 binding is critical for blocking β-catenin nuclear translocation. Furthermore, we identify CD36, a transmembrane fatty acid translocase, as a downstream β-catenin target. DHTS reduces CD36 expression and cellular ATP levels in CRC cells; the reductions are reversed by β-catenin overexpression or stabilization. In CRC-bearing mouse model, DHTS-loaded PLGA-PEG nanoparticles significantly reduce nuclear β-catenin and CD36 expressions in tumors and inhibit tumor growth, consistent with the in vitro findings.

Conclusions

Our study not only reveals the importance of Ser411 in β-catenin function but also paves the path for developing DHTS as a β-catenin inhibitor for CRC therapy.