Honokiol Affects Stem Cell Viability by Suppressing Oncogenic YAP1 Function to Inhibit Colon Tumorigenesis.

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Honokiol (HNK) is a natural biphenolic compound with traditional medicinal uses, including anti-cancer properties.
• Colon cancer remains a significant health concern, with cancer stem cells playing a critical role in tumorigenesis and treatment resistance.

Purpose of the Study:

• To investigate the anti-cancer effects of Honokiol (HNK) on colon cancer cells in vitro and in a colitis-associated cancer model.
• To elucidate the molecular mechanisms underlying HNK's action, focusing on cancer stem cell markers and the Hippo signaling pathway.

Main Methods:

• In vitro studies using colon cancer cell cultures to assess proliferation, colony formation, and apoptosis.
• Molecular docking to predict HNK interaction with DCLK1.
• In vitro kinase assays to evaluate DCLK1 activity.
• Western blotting to analyze protein expression (DCLK1, LGR5, CD44, YAP1, TEAD1).
• In vivo studies using an AOM/DSS-induced colitis-associated cancer model in mice.

Main Results:

• HNK inhibited colon cancer cell proliferation, colony formation, and colonosphere formation, while inducing apoptosis.
• HNK suppressed DCLK1 kinase activity and the expression of stem cell markers LGR5 and CD44.
• HNK treatment led to cytoplasmic sequestration of YAP1 by inducing interaction with PUMA, independent of canonical Hippo pathway phosphorylation.
• In vivo, HNK significantly reduced YAP1, TEAD1, and stem marker expression in a colitis-associated cancer model.

Conclusions:

• Honokiol (HNK) exhibits potent anti-colon cancer activity by targeting cancer stem cells.
• HNK's mechanism involves the induction of PUMA-YAP1 interaction, leading to YAP1 cytoplasmic sequestration and suppression of oncogenic activity.
• These findings suggest HNK as a potential therapeutic agent for preventing colon tumorigenesis.