Specifying protein kinase C functions in melanoma

Abstract

SummaryThe protein kinase C (PKC) family of serine/threonine protein kinases is a heterogeneous group of enzymes receiving and integrating signals involved in both normal melanocyte biology and melanoma pathology. Alterations in PKC enzyme expression and activation contribute to the malignant phenotype of melanoma in both oncogenic and tumor suppressive roles. Delineating the diverse and often context‐dependent functions of PKC enzymes in melanocyte/melanoma biology is key to capitalize on these kinases as drug targets. This review summarizes several of the diverse functions of PKC in melanocyte and melanoma biology with a focus on PKC enzyme regulation and function.

Novel Protein Kinase C-Mediated Control of Orai1 Function in Invasive Melanoma

“…Invasive melanoma cells have been shown previously to exhibit elevated PKC activity (27), and PKC has been shown previously to inhibit SOCE (28,29). Since the loss of SOCE in invasive melanoma was independent of the level of expression, we considered that differential phosphorylation could be a factor.…”

Protein Kinase C (PKC) Isozymes and Cancer

“…Melanoma. PKC , , , , and / are the PKC isozymes expressed in melanoma [333,334]. Among them, PKC is the most important as it is involved in differentiation, proliferation, survival, metastasis, and antiapoptosis of melanoma cells [333,335].…”

“…PKC is detected in normal melanocytes, but is not found in isolated primary or metastatic melanoma cells [333,334]. Introduction of PKC II into melanoma cells suppresses HGF-induced activation of PI3K, tyrosine phosphorylation of adapter protein Gab1, and invasion activity of melanoma cells [345].…”

Cutaneous adverse effects of BRAF inhibitors in metastatic malignant melanoma, a prospective study in 20 patients.

“…3 To transduce signals from mitogenic growth factors in normal melanocytes, Protein Kinase C (PKC) enzymes activate the kinase axis through direct phosphorylation. 4 Normal human melanocytes require chronic PKC activation for growth in culture, and in fact melanocyte culture medium often contains a direct activator of PKC, the phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA), to stimulate melanocyte proliferation. In sharp contrast, melanoma cells are growth inhibited or in some cases killed when cultured in the presence of TPA.…”

“…Thus, common oncogenic changes in MAPK signalling in melanoma appear to substitute for the mitogenic effects of the PKC agonist TPA in melanocytes. 4 BRAF inhibitor therapy causes frequent and significant cutaneous adverse reactions. Most of these reactions are grade 1 or 2 in severity and can be managed without the need to cease or modify the dose of the BRAF inhibitor.…”