Cancer-associated PKC mutations result in loss of function and enhance tumor growth.
Major finding: Cancer-associated PKC mutations result in loss of function and enhance tumor growth.
Concept: PKC mutations disrupt second-messenger binding, processing phosphorylation, or kinase activity.
Impact: These data explain the failure of PKC inhibitors and support restoration of PKC activity in cancer cells.
The protein kinase C (PKC) family functions as receptors for the tumor-promoting phorbol esters, supporting the idea that activation of these isozymes promotes cancer progression. However, PKC isozymes have been shown to act as tumor suppressors in certain contexts, and PKC inhibitors have proven unsuccessful in clinical trials, calling into question the role of PKC in tumorigenesis. To address this issue, Antal and colleagues analyzed 46 PKC mutations identified in human cancers to determine how they affect PKC activity. Intriguingly, none of the mutations were activating; rather, the majority (61%) of mutations analyzed resulted in loss of PKC function by various mechanisms. Although there were no mutational hotspots, PKC inactivating mutations frequently localized to highly conserved residues and were enriched in certain cancers. Cancer-associated mutations in the regulatory C1 and C2 domains, which are required for translocation of PKC to membranes, resulted in ablation of agonist-stimulated PKC activity and membrane translocation due to impaired second-messenger binding. In addition, 16 of 21 kinase domain mutations analyzed were loss-of-function mutations, primarily as a result of defective processing by phosphorylation. Of note, a majority of PKC mutations were heterozygous, suggesting that PKC may be a co-driver of tumorigenesis, and several mutations functioned as dominant negatives to inhibit global PKC activity. Consistent with a tumor-suppressive function of PKC, reversion of a loss-of-function PKCβ mutation to wild-type in colon cancer cells using CRISPR/Cas9-mediated genome editing resulted in increased PKC activity, reduced anchorage-independent growth, and decreased tumor growth in vivo. Furthermore, hemizygous deletion of PKCβ enhanced anchorage-independent growth, suggesting that PKCβ is a haploinsufficient tumor suppressor. These data identify PKC isozymes as tumor suppressors and support the development of therapeutic strategies to restore, rather than inhibit, PKC activity in cancer cells.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.