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.
Highlights
The Wnt/b-catenin pathway, which is activated by the interaction of Wnt1, Wnt3a, and Wnt8 with Frizzled (Fz) receptors and low-density lipoprotein receptor-related protein5/6 (LRP5/6) co-receptors, plays important roles in cell proliferation, differentiation, and oncogenesis [1]
In the absence of a Wnt signal, b-catenin is phosphorylated by both casein kinase 1 (CK1) and glycogen synthase kinase-3b (GSK-3b), which form a complex with adenomatous polyposis coli (APC)/Axin
But not GSK-3bactivity Given that the phosphorylation of b-catenin by GSK-3b and its subsequent association with b-transducin repeatcontaining protein (b-TrCP) leads to b-catenin degradation [13], we examined whether GSK-3b activity is necessary for the degradation of b-catenin induced by CGK062
Summary
The Wnt/b-catenin pathway, which is activated by the interaction of Wnt, Wnt3a, and Wnt with Frizzled (Fz) receptors and low-density lipoprotein receptor-related protein5/6 (LRP5/6) co-receptors, plays important roles in cell proliferation, differentiation, and oncogenesis [1] Central to this pathway is the level of cytosolic b-catenin, which regulates its target genes. Oncogenic mutation in bcatenin or other components of the destruction complex (APC or Axin) are observed in colon cancer, hepatocelluar carcinoma, and prostate cancer [6,7,8] These mutations lead to the excessive accumulation of b-catenin in cytoplasm and b-catenin is translocated into the nucleus, where it complexes with T cell factor/lymphocyte enhancer factor (TCF/LEF) family transcription factors to activate the expression of Wnt/b-catenin responsive genes, such as c-myc, cyclin D1 and metalloproteinase-7 (MMP-7), which play important roles in tumorigenesis and metastasis [9,10,11]. Aberrant activation of the Wnt/b-catenin pathway is a potential therapeutic target for chemoprevention and treatment of various cancers
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
