title: Protein kinase d as a potential chemotherapeutic target for colorectal cancer.
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 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.
authors.affiliation: Authors' Affiliations: Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine; Cancer Therapeutics Program, University of Pittsburgh Cancer Institute; and Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Ning
authors.initials: N
authors.lastname: Wei
authors.forename: Edward
authors.initials: E
authors.lastname: Chu
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.forename: John C
authors.initials: JC
authors.lastname: Schmitz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C089212:protein kinase D; D011493:Protein Kinase C