Abstract
Galangin is a naturally occurring bioflavonoid with anticancer activity against certain human cancers, yet little is known about its mechanism of action. Here, we used a chemical biology approach to reveal that galangin suppresses β-catenin response transcription (CRT), which is aberrantly up-regulated in colorectal and liver cancers, by promoting the degradation of intracellular β-catenin. Inhibition of glycogen synthase kinase-3β (GSK-3β) activity or mutation of the GSK-3β-targeted sequence from β-catenin was unable to abrogate the galangin-mediated degradation of β-catenin. In addition, galangin down-regulated the intracellular β-catenin levels in cancer cells with inactivating mutations of adenomatous polyposis coli (APC) or Axin, which are components of the β-catenin destruction complex. Galangin repressed the expression of β-catenin/T-cell factor-dependent genes, such as cyclin D1 and c-myc, and thus inhibited the proliferation of CRT-positive cancer cells. Structure-activity data indicated that the major structural requirements for galangin-mediated β-catenin degradation are hydroxyl groups at positions 3, 5, and 7. Our findings suggest that galangin exerts its anticancer activity by promoting APC/Axin/GSK-3β-independent proteasomal degradation of β-catenin.
Footnotes
This work was supported by the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family affairs, Republic of Korea [Grant 0920090]; and by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology [Grants 2010-0016043 and 2010-0004711].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.069591.
-
ABBREVIATIONS:
- APC
- adenomatous polyposis coli
- CRT
- β-catenin response transcription
- GSK-3β
- glycogen synthase kinase-3β
- Wnt3a-CM
- Wnt3a conditioned medium
- β-TrCP
- β-transducin repeat-containing protein
- HEK
- human embryonic kidney
- hFz-1
- human Frizzled-1
- DMSO
- dimethyl sulfoxide
- MG-132
- N-benzyoloxycarbonyl (Z)-Leu-Leu-leucinal
- TCF
- T-cell factor
- CK1
- casein kinase 1
- FL
- firefly luciferase
- SEAP
- secreted alkaline phosphatase
- siRNA
- small interfering RNA.
- Received October 22, 2010.
- Accepted March 14, 2011.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|