Wnt/β-catenin signaling mediates the antitumor activity of magnolol in colorectal cancer cells.

Abstract

Abnormal activation of the canonical Wnt/β-catenin pathway and up-regulation of the β-catenin/T-cell factor (TCF) response to transcriptional signaling play a critical role early in colorectal carcinogenesis. Therefore, Wnt/β-catenin signaling is considered an attractive target for cancer chemotherapeutic or chemopreventive agents. Small molecules derived from the natural products were used in our cell-based reporter gene assay to identify potential inhibitors of Wnt/β-catenin signaling. Magnolol, a neolignan from the cortex of Magnolia obovata, was identified as a promising candidate because it effectively inhibited β-catenin/TCF reporter gene (TOPflash) activity. Magnolol also suppressed Wnt3a-induced β-catenin translocation and subsequent target gene expression in human embryonic kidney 293 cells. To further investigate the precise mechanisms of action in the regulation of Wnt/β-catenin signaling by magnolol, we performed Western blot analysis, real-time reverse transcriptase-polymerase chain reactions, and an electrophoretic mobility shift assay in human colon cancer cells with aberrantly activated Wnt/β-catenin signaling. Magnolol inhibited the nuclear translocation of β-catenin and significantly suppressed the binding of β-catenin/TCF complexes onto their specific DNA-binding sites in the nucleus. These events led to the down-regulation of β-catenin/TCF-targeted downstream genes such as c-myc, matrix metalloproteinase-7, and urokinase-type plasminogen activator in SW480 and HCT116 human colon cancer cells. In addition, magnolol inhibited the invasion and motility of tumor cells and exhibited antitumor activity in a xenograft nude mouse model bearing HCT116 cells. These findings suggest that the growth inhibition of magnolol against human colon cancer cells can be partly attributed to the regulation of the Wnt/β-catenin signaling pathway.

• Authors: You-Jin Kang, Hyen Joo Park, Hwa-Jin Chung, Hye-Young Min, Eun Jung Park, Min Ai Lee, Yoonho Shin, Sang Kook Lee
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 82 Issue 2 Pg. 168-77 (Aug 2012) ISSN: 1521-0111 [Electronic] United States
• PMID: 22550094 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Biphenyl Compounds
• CTNNB1 protein, human
• Lignans
• WNT3A protein, human
• Wnt3A Protein
• beta Catenin
• magnolol

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology, therapeutic use)
• Biphenyl Compounds (pharmacology, therapeutic use)
• Colorectal Neoplasms (drug therapy, pathology)
• Female
• HCT116 Cells
• HEK293 Cells
• Humans
• Lignans (pharmacology, therapeutic use)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Signal Transduction (drug effects, physiology)
• Wnt3A Protein (physiology)
• Xenograft Model Antitumor Assays (methods)
• beta Catenin (physiology)