Abstract
Over 80% of colon cancer development and progression is a result of the dysregulation of β-catenin signaling pathway. Herein, for the first time, we demonstrate that a serine-threonine kinase, Protein Kinase D1 (PKD1), modulates the functions of β-catenin to suppress colon cancer growth. Analysis of normal and colon cancer tissues reveals downregulation of PKD1 expression in advanced stages of colon cancer and its co-localization with β-catenin in the colon crypts. This PKD1 downregulation corresponds with the aberrant expression and nuclear localization of β-catenin. In-vitro investigation of the PKD1-β-catenin interaction in colon cancer cells reveal that PKD1 overexpression suppresses cell proliferation and clonogenic potential and enhances cell-cell aggregation. We demonstrate that PKD1 directly interacts with β-catenin and attenuates β-catenin transcriptional activity by decreasing nuclear β-catenin levels. Additionally, we show that inhibition of nuclear β-catenin transcriptional activity is predominantly influenced by nucleus targeted PKD1. This subcellular modulation of β-catenin results in enhanced membrane localization of β-catenin and thereby increases cell-cell adhesion. Studies in a xenograft mouse model indicate that PKD1 overexpression delayed tumor appearance, enhanced necrosis and lowered tumor hypoxia. Overall, our results demonstrate a putative tumor-suppressor function of PKD1 in colon tumorigenesis via modulation of β-catenin functions in cells.
Highlights
Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer death in the US with approximately 51,000 deaths per year [1]
Studies have identified that inhibitors of the PTEN/ Akt/GSK3β signaling cascade and regulation of β-catenin act as potential agents to effectively target cancer stem cells and tumorigenic cancer cells [3, 4]. β-catenin is a highly conserved, bi-functional protein that functions as a transcription factor in the Wnt signaling pathway to regulate cell proliferation and differentiation [5, 6]
We examined the staining pattern of Protein Kinase D1 (PKD1) expression in tissue of normal colon and colon cancer and demonstrated that PKD1 co-localized with β-catenin in normal colon tissues
Summary
Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer death in the US with approximately 51,000 deaths per year [1]. Mutations in APC, Axin, or these N-terminal phosphorylation sites of β-catenin are found in multiple types of human cancers, where these mutations elevate β-catenin posttranscriptional stability, signaling [8] and formation of nuclear β-catenin/ TCF complexes [9]. In these scenarios, β-catenin localizes to the nucleus and enhances the transcription of protooncogenes such as c-Myc, c-Jun and Cyclin D1, resulting in initiation and progression of cancer [5, 6]
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