Abstract
The Wnt/β-catenin signaling pathway plays a key role in the progression of human colorectal cancers (CRCs) and is one of the leading targets of chemotherapy agents developed for CRC. The present study aimed to investigate the anti-cancer effects and molecular mechanisms of 19-O-triphenylmethyl andrographolide (RS-PP-050), an andrographolide analogue and determine its activity in the Wnt/β-catenin pathway. RS-PP-050 was found to potently inhibit the proliferation and survival of HT-29 CRC cells. It induces cell cycle arrest and promotes apoptotic cell death which was associated with the activation of PARP-1 and p53. Furthermore, RS-PP-050 exerts inhibitory effects on β-catenin transcription by suppressing T-cell factor/lymphocyte enhancer factor (TCF/LEF) activity in cells overexpressing β-catenin and by down-regulating the endogenous expression of Wnt target genes. RS-PP-050 also decreased the protein expression of the active form of β-catenin but functions independently of GSK-3β, a negative regulator of Wnt. Interestingly, RS-PP-050 extensively blocks phosphorylation at Ser675 of β-catenin which links to interference of the nuclear translocation of β-catenin and might contribute to Wnt inactivation. Collectively, our findings reveal the underlying anti-cancer mechanism of an andrographolide analogue and provide useful insight for exploiting a newly chemotherapeutic agent in Wnt/β-catenin-overexpressing CRC cells.
Highlights
In the absence of Wnt ligands, the key effector of this signaling, β-catenin, is sequestered in a destruction complex composed of adenomatous polyposis coli (APC), casein kinase 1α (CK1α), Axin, and glycogen synthase kinase-3β (GSK-3β) which maintains the activity of cytosolic β-catenin at a low
This results in the accumulation of free β-catenin able to translocate into the nucleus to form a complex with T-cell factor/lymphocyte enhancer factor (TCF/LEF) family transcription factors to activate the transcription of Wnt target genes such as c-myc, cyclin D1, matrix metalloproteinase-7 (MMP-7), and survivin
We demonstrated that our andrographolide analogue, RS-PP-050 effectively inhibited TCF/LEF transcriptional activity of canonical Wnt/β-catenin signaling
Summary
The binding of Wnt ligands to the Frizzled (Fz) receptor and the low density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptor on the plasma membrane triggers the disassembly of the destruction complex This results in the accumulation of free β-catenin able to translocate into the nucleus to form a complex with TCF/LEF family transcription factors to activate the transcription of Wnt target genes such as c-myc, cyclin D1, matrix metalloproteinase-7 (MMP-7), and survivin. Loss or gain of function by genetic alterations of Wnt components including APC, Axin, and β-catenin, cause β-catenin to escape degradation imposed by the upstream negative regulators, allowing deregulated β-catenin transcriptional activity in the nucleus[11] Because of these genetic mutations in the Wnt pathway components, inhibition upstream of β-catenin may produce the discernable effect to inactivate Wnt signaling. Aberrant accumulation of β-catenin in nucleus caused by Wnt gene mutations in CRC is a potential target to search for specific chemotherapeutic agents[15,16]
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