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<p>Most persons with colorectal cancer (CRC) carry adenomatous polyposis coli (APC) truncation leading to aberrant Wnt–β-catenin signaling; however, effective targeted therapy for them is lacking as the mechanism by which APC truncation drives CRC remains elusive. Here, we report that the cholesterol level in the inner leaflet of the plasma membrane (IPM) is elevated in all tested APC-truncated CRC cells, driving Wnt-independent formation of Wnt signalosomes through Dishevelled (Dvl)–cholesterol interaction. Cholesterol–Dvl interaction inhibitors potently blocked β-catenin signaling in APC-truncated CRC cells and suppressed their viability. Because of low IPM cholesterol level and low Dvl expression and dependence, normal cells including primary colon epithelial cells were not sensitive to these inhibitors. In vivo testing with a xenograft mouse model showed that our inhibitors effectively suppressed truncated APC-driven tumors without causing intestinal toxicity. Collectively, these results suggest that the most common type of CRC could be effectively and safely treated by blocking the cholesterol–Dvl–β-catenin signaling axis.</p><p></p>

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Cholesterol-targeting Wnt–β-catenin signaling inhibitors for colorectal cancer

  • 期刊论文

  • 发表日期：

    2025年4月16日

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  • Ashutosh Sharma,
  • Julian Zalejski,
  • Shruti Vijay Bendre,
  • Simona Kavrokova,
  • Hale Siir Hasdemir,
  • Defne Gorgun Ozgulbas,
  • Jiachen Sun,
  • Koralege C. Pathmasiri,
  • Ruicheng Shi,
  • Ahmed Aloulou,
  • Kyli Berkley,
  • Charles F. Delisle,
  • Young Wang,
  • Erin Weisser,
  • Pawanthi Buweneka,
  • Dominick Pierre-Jacques,
  • Sayandeb Mukherjee,
  • Diana A. Abbasi,
  • Daesung Lee,
  • Bo Wang,
  • Vladimir Gevorgyan,
  • Stephanie M. Cologna,
  • Emad Tajkhorshid,
  • Erik R. Nelson,
  • Wonhwa Cho

摘要

Most persons with colorectal cancer (CRC) carry adenomatous polyposis coli (APC) truncation leading to aberrant Wnt–β-catenin signaling; however, effective targeted therapy for them is lacking as the mechanism by which APC truncation drives CRC remains elusive. Here, we report that the cholesterol level in the inner leaflet of the plasma membrane (IPM) is elevated in all tested APC-truncated CRC cells, driving Wnt-independent formation of Wnt signalosomes through Dishevelled (Dvl)–cholesterol interaction. Cholesterol–Dvl interaction inhibitors potently blocked β-catenin signaling in APC-truncated CRC cells and suppressed their viability. Because of low IPM cholesterol level and low Dvl expression and dependence, normal cells including primary colon epithelial cells were not sensitive to these inhibitors. In vivo testing with a xenograft mouse model showed that our inhibitors effectively suppressed truncated APC-driven tumors without causing intestinal toxicity. Collectively, these results suggest that the most common type of CRC could be effectively and safely treated by blocking the cholesterol–Dvl–β-catenin signaling axis.