title: Protein kinase D1 attenuates tumorigenesis in colon cancer by modulating β-catenin/T cell factor activity.
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.
authors.affiliation: Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD, USA. .
authors.forename: Vasudha
authors.initials: V
authors.lastname: Sundram
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee. .
authors.forename: Aditya
authors.initials: A
authors.lastname: Ganju
authors.affiliation: Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD, USA.
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Hughes
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Sheema
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Chauhan
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Meena
authors.initials: M
authors.lastname: Jaggi
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D019073:HT29 Cells; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism; D051820:TCF Transcription Factors / Q000378:metabolism*; D050396:TRPP Cation Channels / Q000096:biosynthesis / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051820:TCF Transcription Factors; D050396:TRPP Cation Channels; D051176:beta Catenin; C495270:CTNNB1 protein, human