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 G(2)-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-κB 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.