Small molecule-based promotion of PKCα-mediated β-catenin degradation suppresses the proliferation of CRT-positive cancer cells.
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.
Department of Advanced Fermentation Fusion Science and Technology, Kookmin University, Seoul, Republic of Korea.
Jungsug
J
Gwak
Jee-Hyun
JH
Lee
Young-Hwa
YH
Chung
Gyu-Yong
GY
Song
Sangtaek
S
Oh
D000179:Acrylates / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002839:Chromans / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D059748:Proteolysis / Q000187:drug effects*; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism
C540133:3-(3,4-dihydroxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H,8H-pyrano(3,2-g)chromen-3-yl-ester; D000179:Acrylates; D000970:Antineoplastic Agents; D002839:Chromans; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha; D038362:Glycogen Synthase Kinase 3