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Small Molecule-Based Promotion of PKCa-Mediated ß-Catenin Degradation Suppresses the Proliferation of CRT-Positive Cancer Cells
Published: Friday, October 05, 2012
Author: Jungsug Gwak et al.

by Jungsug Gwak, Jee-Hyun Lee, Young-Hwa Chung, Gyu-Yong Song, Sangtaek Oh

Aberrant accumulation of intracellular ß-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/ß-catenin signaling. CGK062 promoted protein kinase Ca (PKCa)-mediated phosphorylation of ß-catenin at Ser33/Ser37, marking it for proteasomal degradation. This reduced intracellular ß-catenin levels and consequently antagonized ß-catenin response transcription (CRT). Pharmacological inhibition or depletion of PKCa abrogated CGK062-mediated phosphorylation and degradation of ß-catenin. In addition, CGK062 repressed the expression of the genes encoding cyclin D1, c-myc, and axin-2, ß-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 PKCa-mediated ß-catenin phosphorylation/degradation. Therefore, CGK062 has significant therapeutic potential for the treatment of CRT-positive cancers.