Protein kinase c α but not PKCζ suppresses intestinal tumor formation in ApcMin/+ mice

Members of the protein kinase C (PKC) family of serine/threonine kinases play key regulatory roles in numerous cellular processes, including differentiation and proliferation. Of the 11 mammalian PKC isoforms known, several have been implicated in tumor development and progression. However, in most cases, isotype specificity is poorly defined, and even contrary functions for a single PKC have been reported mostly because appropriate molecular and genetic tools were missing to specifically assess the contribution of single PKC isoforms in vivo. In this report, we therefore used PKC genetic targeting to study the role of PKC alpha and PKC zeta in colorectal cancer. Both isoforms were found to be strongly down-regulated in intestinal tumors of Apc(Min/+) mice. A deletion of PKC zeta did not affect tumorigenesis in this animal model. In contrast, PKC alpha-deficient Apc(Min/+) mice developed more aggressive tumors and died significantly earlier than their PKC alpha-proficient litter-mates. Even without an additional Apc mutation, PKC alpha knockout mice showed an elevated tendency to develop spontaneous intestinal tumors. Transcriptional profiling revealed a role for this kinase in regulating epidermal growth factor receptor (EGFR) signaling and proposed a synergistic mechanism for EGFR/activator protein and WNT/APC pathways in mediating intestinal tumor development.