Lupeol Inhibits Stemness in Colon Cancer-Stem Like Cells and Promotes Chemosensitivity via Degrading β-Catenin

Abstract

Objective: Colon cancer stem-like cells (CSCs) are self-renewing and tumor-initiating. They are resistant to chemotherapy drugs, such as doxorubicin. The presence of this subpopulation leads to poor treatment outcomes, recurrence and metastasis in colon cancer. Therefore, current therapeutic strategies targeting stem cell self-renewal pathways are a reasonable approach for cancer prevention and treatment. In this study, we aimed to evaluate the potential antitumor effects of Lup-20(29)-en-3b-ol (lupeol) by targeting this subpopulation. Methods: CSCs were enriched by being cultured in serum-free medium, and the effects of lupeol on CSC malignancies were measured. These effects included proliferation, migration, invasion and tumor formation. The stemness hallmarks were measured by western blotting. The effects of lupeol on the chemosensitivity of CSCs were measured by detecting apoptosis. Results: We found that lupeol did not affect cell proliferation and viability but remarkably inhibited the invasion and tumor formation abilities of CSCs. When colon cancer cells were cultured in serum-free medium, lupeol inhibited sphere formation and decreased stemness hallmarks. Moreover, when lupeol was added to the formed spheres for 48 h, the spheres dissociated and tended to grow adherently. Additionally, only Nestin and β-catenin, but not Sox2, Oct4 (Octamer-binding transcription factor) or Nanog, were significantly decreased. These results demonstrate that lupeol disturbed stemness in colon cancer, potentially by regulating Nestin or β-catenin. Additionally, lupeol treatment or β-catenin inhibitor treatment significantly increased DOX (Doxorubicin)-induced apoptosis, demonstrating that lupeol increased chemosensitivity potentially by downregulating β-catenin in CSCs. Conclusions: Taken together, our results demonstrate that lupeol is a potential chemoagent that specifically targets CSCs in colon cancer.