Abstract
Aberrant accumulation of intracellular β-catenin is a well recognized characteristic of several cancers, including prostate, colon, and liver cancers, and is a potential target for development of anticancer therapeutics. Here, we used cell-based small molecule screening to identify CGK062 as an inhibitor of Wnt/β-catenin signaling. CGK062 promoted protein kinase Cα (PKCα)-mediated phosphorylation of β-catenin at Ser33/Ser37, marking it for proteasomal degradation. This reduced intracellular β-catenin levels and consequently antagonized β-catenin response transcription (CRT). Pharmacological inhibition or depletion of PKCα abrogated CGK062-mediated phosphorylation and degradation of β-catenin. In addition, CGK062 repressed the expression of the genes encoding cyclin D1, c-myc, and axin-2, β-catenin target genes, and thus inhibited the growth of CRT-positive cancer cells. Furthermore, treatment of nude mice bearing PC3 xenograft tumors with CGK062 at doses of 50 mg/kg and 100 mg/kg (i.p.) significantly suppressed tumor growth. Our findings suggest that CGK062 exerts its anticancer activity by promoting PKCα-mediated β-catenin phosphorylation/degradation. Therefore, CGK062 has significant therapeutic potential for the treatment of CRT-positive cancers.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acrylates / pharmacology*
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Animals
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Chromans / pharmacology*
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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HEK293 Cells
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Humans
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Inhibitory Concentration 50
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Mice
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Mice, Nude
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Phosphorylation
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Protein Kinase C-alpha / metabolism*
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Protein Processing, Post-Translational
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Proteolysis / drug effects*
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Transcription, Genetic
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Wnt Signaling Pathway
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Xenograft Model Antitumor Assays
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beta Catenin / metabolism*
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beta-Transducin Repeat-Containing Proteins / metabolism
Substances
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3-(3,4-dihydroxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H,8H-pyrano(3,2-g)chromen-3-yl-ester
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Acrylates
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Antineoplastic Agents
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Chromans
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beta Catenin
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beta-Transducin Repeat-Containing Proteins
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Glycogen Synthase Kinase 3 beta
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PRKCA protein, human
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Protein Kinase C-alpha
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Glycogen Synthase Kinase 3
Grants and funding
This work was supported by Basic Science Research Program through the National Reserch Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A2A2A01002941). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.