Protein kinase D1 attenuates tumorigenesis in colon cancer by modulating β-catenin/T cell factor activity
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Vasudha Sundram1, Aditya Ganju2, Joshua E. Hughes1, Sheema Khan2, Subhash C. Chauhan2, Meena Jaggi2
1Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD, USA
2Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee.
Meena Jaggi, email: [email protected]
Key words: Colon Cancer, PKD1, β-catenin, T cell factor activity (TCF), Tumor suppressor, Cell motility, Cell invasion
Received: June 7, 2014 Accepted: July 23, 2014 Published: August 4, 2014
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.
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