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Protein kinase D1 attenuates tumorigenesis in colon cancer by modulating ?-catenin/T cell factor activity.

ABSTRACT: Over 80% of colon cancer development and progression is a result of the dysregulation of ?-catenin signaling pathway. Herein, for the first time, we demonstrate that a serine-threonine kinase, Protein Kinase D1 (PKD1), modulates the functions of ?-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 ?-catenin in the colon crypts. This PKD1 downregulation corresponds with the aberrant expression and nuclear localization of ?-catenin. In-vitro investigation of the PKD1-?-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 ?-catenin and attenuates ?-catenin transcriptional activity by decreasing nuclear ?-catenin levels. Additionally, we show that inhibition of nuclear ?-catenin transcriptional activity is predominantly influenced by nucleus targeted PKD1. This subcellular modulation of ?-catenin results in enhanced membrane localization of ?-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 ?-catenin functions in cells.

SUBMITTER: Sundram V

PROVIDER: S-EPMC4196169 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Protein kinase D1 attenuates tumorigenesis in colon cancer by modulating β-catenin/T cell factor activity.

Sundram Vasudha V Ganju Aditya A Hughes Joshua E JE Khan Sheema S Chauhan Subhash C SC Jaggi Meena M

Oncotarget 20140801 16

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 corre ...[more]

PMID: 25149539

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Project description:Emerging evidence has demonstrated the critical roles for both androgen and Wnt pathways in prostate tumorigenesis. A recent integrative genomic analysis of human prostate cancers (PCas) has revealed a unique enrichment of androgen and Wnt signaling in early-onset PCas, implying their clinical significance in the disease. Additionally, interaction between the androgen receptor (AR) and β-catenin has long been detected in PCa cells. However, the consequence of this interaction in prostate tumorigenesis is still unknown. Because mutations in adenomatous polyposis coli, β-catenin and other components of the destruction complex are generally rare in PCas, other mechanisms of aberrant Wnt signaling activation have been speculated. To address these critical questions, we developed Ctnnb1(L(ex3)/+)/R26hAR(L/+):PB-Cre4 mice, in which transgenic AR and stabilized β-catenin are co-expressed in prostatic epithelial cells. We observed accelerated tumor development, aggressive tumor invasion and a decreased survival rate in Ctnnb1(L(ex3)/+)/R26hAR(L/+):PB-Cre4 compound mice compared with age-matched Ctnnb1(L(ex3)/+):PB-Cre4 littermate controls, which only have stabilized β-catenin expression in the prostate. Castration of the above transgenic mice resulted in significant tumor regression, implying an essential role of androgen signaling in tumor growth and maintenance. Implantation of the prostatic epithelial cells isolated from the transgenic mice regenerated prostate intraepithelial neoplasias and prostatic adenocarcinoma lesions. Microarray analyses of transcriptional profiles showed more robust enrichment of known tumor- and metastasis-promoting genes: Spp1, Egr1, c-Myc, Sp5, and Sp6 genes, in samples isolated from Ctnnb1(L(ex3)/+)/R26hAR(L/+):PB-Cre4 compound mice than those from Ctnnb1(L(ex3)/+):PB-Cre4 and R26hAR(L/+):PB-Cre4 littermate controls. Together, these data demonstrate a confounding role of androgen signaling in β-catenin-initiated oncogenic transformation in prostate tumorigenesis.

Dataset Information

Protein kinase D1 attenuates tumorigenesis in colon cancer by modulating ?-catenin/T cell factor activity.

Publications

Protein kinase D1 attenuates tumorigenesis in colon cancer by modulating β-catenin/T cell factor activity.

Similar Datasets

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