Protein kinase D as a potential chemotherapeutic target for colorectal cancer

Ning Wei, Edward Chu, Peter Wipf, John C. Schmitz

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Protein kinase D (PKD) signaling plays a critical role in the regulation of DNA synthesis, proliferation, cell survival, adhesion, invasion/migration, motility, and angiogenesis. To date, relatively little is known about the potential role of PKD in the development and/or progression of human colorectal cancer. We evaluated the expression of different PKD isoforms in colorectal cancer and investigated the antitumor activity of PKD inhibitors against human colorectal cancer. PKD2 was the dominant isoform expressed in human colon cancer cells. PKD3 expression was also observed but PKD1 expression, at both the RNA and protein levels, was not detected. Suppression of PKD using the small molecule inhibitors CRT0066101 and kb-NB142-70 resulted in low micromolar in vitro antiproliferative activity against multiple human colorectal cancer cell lines. Drug treatment was associated with dose-dependent suppression of PKD2 activation. Incubation with CRT0066101 resulted in G2-M phase arrest and induction of apoptosis in human colorectal cancer cells. Further studies showed that CRT0066101 treatment gave rise to a dose-dependent increase in expression of cleaved PARP and activated caspase-3, in addition to inhibition of AKT and ERK signaling, and suppression of NF-kB activity. Transfection of PKD2-targeted siRNAs resulted in similar effects on downstream pathways as observed with small molecule inhibitors. Daily administration of CRT0066101 resulted in significant inhibition of tumor growth in HCT116 xenograft nude mice. Taken together, our studies show that PKD plays a significant role in mediating growth signaling in colorectal cancer and may represent a novel chemotherapeutic target for the treatment of colorectal cancer.

Original languageEnglish (US)
Pages (from-to)1130-1141
Number of pages12
JournalMolecular cancer therapeutics
Volume13
Issue number5
DOIs
StatePublished - May 2014
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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