| Abstract |
Inactivating mutations of the tumor suppressor Adenomatosis Polyposis Coli (APC), which are found in familial adenomatosis polyposis and in 80% of sporadic colorectal cancers (CRC), result in constitutive activation of the Wnt/?-catenin pathway and tumor development in the intestine. These mutations disconnect the Wnt/?-catenin pathway from its Wnt extracellular signal by inactivating the APC/GSK3-?/axin destruction complex of ?-catenin. This results in sustained nuclear accumulation of ?-catenin, followed by ?-catenin-dependent co-transcriptional activation of Wnt/?-catenin target genes. Thus, mechanisms acting downstream of APC, such as those controlling ?-catenin stability and/or co-transcriptional activity, are attractive targets for CRC treatment. Protein Kinase C-? (PKC?) phosphorylates the orphan receptor ROR? that then inhibits ?-catenin co-transcriptional activity. PKC? also phosphorylates ?-catenin, leading to its degradation by the proteasome. Here, using both in vitro (DLD-1 cells) and in vivo (C57BL/6J mice) PKC? knock-in models, we investigated whether enhancing PKC? function could be beneficial in CRC treatment. We found that PKC? is infrequently mutated in CRC samples, and that inducing PKC? function is not deleterious for the normal intestinal epithelium. Conversely, di-terpene ester-induced PKC? activity triggers CRC cell death. Together, these data indicate that PKC? is a relevant drug target for CRC treatment. |
Institut de Recherche en Cancérologie de
