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

Vasudha Sundram, Aditya Ganju, Joshua E. Hughes, Sheema Khan, Subhash Chauhan, Meena Jaggi

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6867-6884
Number of pages18
JournalOncotarget
Volume5
Issue number16
DOIs
StatePublished - Jan 1 2014

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TCF Transcription Factors
Catenins
Colonic Neoplasms
Protein Kinases
Carcinogenesis
Colon
Down-Regulation
Tumor Suppressor Proteins
Cell Aggregation
Protein-Serine-Threonine Kinases
Heterografts
Cell Adhesion

All Science Journal Classification (ASJC) codes

  • Oncology

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Protein Kinase D1 attenuates tumorigenesis in colon cancer by modulating β-catenin/T cell factor activity. / Sundram, Vasudha; Ganju, Aditya; Hughes, Joshua E.; Khan, Sheema; Chauhan, Subhash; Jaggi, Meena.

In: Oncotarget, Vol. 5, No. 16, 01.01.2014, p. 6867-6884.

Research output: Contribution to journalArticle

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