Cancer-Associated Protein Kinase C Mutations Reveal Kinase’s Role as Tumor Suppressor

Abstract

SUMMARY Protein kinase C (PKC) isozymes have remained elusive cancer targets despite the unambiguous tumor promoting function of their potent ligands, phorbol esters, and the prevalence of their mutations. We analyzed 8% of PKC mutations identified in human cancers and found that, surprisingly, most were loss of function and none were activating. Loss-of-function mutations occurred in all PKC subgroups and impeded second-messenger binding, phosphorylation, or catalysis. Correction of a loss-of-function PKCβ mutation by CRISPR-mediated genome editing in a patient-derived colon cancer cell line suppressed anchorage-independent growth and reduced tumor growth in a xenograft model. Hemizygous deletion promoted anchorage-independent growth, revealing that PKCβ is haploinsufficient for tumor suppression. Several mutations were dominant negative, suppressing global PKC signaling output, and bioinformatic analysis suggested that PKC mutations cooperate with co-occurring mutations in cancer drivers. These data establish that PKC isozymes generally function as tumor suppressors, indicating that therapies should focus on restoring, not inhibiting, PKC activity.

Natural Product Vibsanin A Induces Differentiation of Myeloid Leukemia Cells through PKC Activation

“…In this context, classic PKC agonists such as PMA, which showed tumor-promoting effects, and bryostatin-1, which failed as a therapeutic, all downregulate PKC and likely result in the inhibition of PKC activity. Conversely, vibsanin A activated PKC with less downregulation of them in leukemia cells, suggesting a promising clinical potential (50). Overall, the potent antileukemic activity and the absence of inflammatory activity with predicted antipromoting potential with vibsanin A is encouraging.…”

“…In light of this, our findings therefor supported the preliminary conclusion that vibsanin A is not tumor promoting but antipromoting. Indeed, Antal and colleagues have recently established that PKC isozymes generally function as tumor suppressors, indicating that therapies should focus on restoring, not inhibiting, PKC activity (50). In this context, classic PKC agonists such as PMA, which showed tumor-promoting effects, and bryostatin-1, which failed as a therapeutic, all downregulate PKC and likely result in the inhibition of PKC activity.…”

Glycogen Synthase Kinase 3β Is Positively Regulated by Protein Kinase Cζ-Mediated Phosphorylation Induced by Wnt Agonists

“…PKC isozymes are commonly dysregulated in many types of cancers, such as colon cancer, and it has been demonstrated that they may act both as oncogenes (21) and as tumor suppressors (22), depending on the cell context and on which protein adaptors interact with PKC isoforms. In this respect, the atypical isoforms, PKC and PKC, have been demonstrated to be critical components of cell survival signal transduction pathways, frequently suppressing apoptosis by activation of prosurvival NF-B and MAPK signaling pathways (21,23,24), but it has also been reported that the loss of PKC in mice results in enhanced intestinal tumorigenesis and in increased stem cell activity (25,26).…”

Anticorpos conformacionais para PKCs clássicas e suas aplicações

“…Além disso, recentemente Antal e colaboradores (2015) mostraram que a expressão das PKCs é geralmente reduzida em tumores e que a maioria das mutações nessas quinases, encontradas em diferentes tipos de câncer, causam uma diminuição ou perda da atividade das PKCs. Ainda, a correção de uma mutação na PKC que causava perda de função dessa PKC, em uma linhagem de câncer de cólon, promoveu restauração da atividade da PKC, aumento da expressão da mesma e da PKC; além da redução do tumor, indicando que as PKCs podem atuar não apenas como promotoras de tumores, mas também como supressoras (Antal, Hudson, et al, 2015). Esses trabalhos demonstram que o papel das isoenzimas das PKCs no câncer é ainda controverso e que estudos visando verificar não apenas a expressão, mas também a atividade das PKCs devem ser conduzidos.…”

“…Interessantemente, poucas mutações em PKCs foram encontradas em câncer de mama (Antal, Hudson, et al, 2015) (Bass et al, 2007;Humphries et al, 2014).…”