Atypical Protein Kinase Cs in Melanoma Progression

Melanoma is one of the fastest growing types of cancer worldwide in terms of incidence. To date, reports show over 92,000 new cases in the United States in 2018. Previously, we introduced protein kinase C-iota (PKC- ι ) as an oncogene in melanoma. PKC- ι promotes survival and cancer progression along with PKC-zeta( ζ ). In addition, we reported that PKC- ι induced metastasis of melanoma cells by increasing Vimentin dynamics. Our previous results showed that PKC- ι inhibition downregulated epithelial-mesenchymal transition (EMT), while inducing apoptosis. In this chapter, we summarized these findings which were based on the in-vitro applications of five specific atypical PKC (aPKC) inhibitors. In addition, the underlying mechanisms of the transcriptional regulation of PRKCI gene expression in melanoma is also discussed. Results demonstrated that c-Jun promotes PRKCI expression along with Interleukin (IL)-6/8. Furthermore, forkhead box protein O1 (FOXO1) acts as a downregulator of PRKCI expression upon stimulation of IL-17E and intercellular adhesion molecule 1 (ICAM-1) in melanoma cells. Overall, the chapter summarizes the importance of PKC- ι / ζ in the progression of melanoma and discusses the cellular signaling pathways that are altered upon inhibitor applications. Finally, we established that aPKCs are effective novel biomarkers for use in the design of novel targeted therapeutics for melanoma. effects of TNF- α stimulation on the expression of aPKCs TNF- α is a cytokine, involved in the early phase of acute inflammation by activating NF- κ B. TNF- α stimulation significantly increased NF- κ B levels in both cytosol and nuclei. Increased NF- κ B production promotes increases in total and phosphorylated aPKCs and increased the levels of Bcl-2, which enhanced melanoma cell survival. We observed amplified levels of I κ B and NF- κ B, which together enhanced the phosphorylation of I κ B due to the augmented levels of aPKCs [23]. On the other hand, PI3K/AKT signaling can be diminished by inhibiting aPKCs via downregulation of NF- κ B. These results confirm that both PKC- ζ and PKC- ι are rooted in cellular survival via NF- κ B and PI3K/AKT pathways. SNAIL1 and PRRX1 are two very important transcription factors and they drive EMT process by upregulating Vimentin while downregulating E-cadherin. PKC- ι activates Vimentin by phosphorylation and this initiates disassembly of VIF and facilitates cellular motility. During this process, cadherin junctions are disrupted as a result of loss of E-cadherin and β -catenin is translocated to nucleus to upregulate the production of facilitating proteins such as CD44 which further stimulate migration and EMT. Activated Vimentin changes cell polarity to maintain the mesenchymal phenotype of melanoma cells in-vitro. in melanoma cells due to elevated transcriptional activity of c-Jun with the aid of PI3K/AKT, NF- κ B, STAT3/5 signaling. The specific inhibition of PKC- ι initiates a disruption to rapid PKC- ι expression cycle in melanoma where the reduced activity of PKC- ι downregulates the NF- κ B pathway and its transcriptional activity, which in turn diminishes the expression of IL-6/8. As a result of this AKT activity reduction, FOXO1 gets upregulated. FOXO1 turns out to be the most important TF regulating PKC- ι expression after the disruption initiated as a result of PKC- ι inhibition. Dominant FOXO1 negatively regulates the expression of PKC- ι and also diminishes the JNK activity to retard its activation of c-Jun. we found c-Jun as the transcription component which upregulates PKC- ι expression. The downregulation of IL-6 and IL-8 expression leads to the lessened STAT3/5 signaling, which causes c-Jun transcriptional reduction. This whole process continues and leads to the further downregulation of NF- κ B, AKT and JNK/c-Jun while upregulating FOXO1, which leads to the continuation of the attenuation of PKC- ι expression. As a result, the total PKC- ι level decreases in melanoma cells.