Small molecule-based promotion of PKC?-mediated ?-catenin degradation suppresses the proliferation of CRT-positive cancer cells.

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

SUBMITTER: Gwak J 

PROVIDER: S-EPMC3465275 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature