Modulating PKCα Activity to Target Wnt/β-Catenin Signaling in Colon Cancer

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