Melanoma is a type of cancer occurs in melanocytes. Approximately 90% of melanoma occurs in skin (cutaneous melanoma) but can rarely arise from the mucosal surfaces or areas which neural cells migrate. Examples are eye, intestine and mouth [Eur. J. Cancer, 69: 39-42 (2016)]. 76,380 of new cases and 10,130 number of deaths are expected in 2016 in the USA due to melanoma [ (11/05/2016)]. Atypical PKCs contains two structurally and functionally distinct isozymes in human which are PKC-ι (iota) and PKC-ζ (zeta). They are believed to be involved in cell cycle progression, tumorigenesis, cell survival and cell migration. We believe that atypical PKCs play an important role in cell motility of melanoma by involving the signaling pathways which induces EMT-type III (Epithelial to Mesenchymal Transition). In normal melanocytes, PKC-ζ was found in low levels and PKC-ι was not detected. But both proteins are detected in very high levels in malignant melanoma [Melenoma Res. 12:201-209 (2002)]. In the current study, we have investigated the effects of novel atypical PKC inhibitors [4-(5-amino-4-carbamoylimidazol-1-yl)-2, 3-dihydroxycyclopentyl] methyl dihydrogen phosphate (ICA-1) which is specific to PKC-ι and 8-hydroxy-1, 3, 6-naphthalenetrisulfonic acid (Compound-50) which is specific to PKC-ζ on the cell proliferation, apoptosis and cell migration of two malignant melanoma cell lines (SK-MEL-2 and MeWo) compared to a normal melanocyte cell line (PCS-200-013). We showed that both inhibitors can decrease the levels of total and phosphorylated levels of PKC-ζ and PKC-ι. Furthermore, both inhibitors increased the levels of E-cadherin and decreased the levels of Vimentin which is a mesenchymal marker associated with EMT. Treatments with inhibitors altered the levels of CD44, a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion, migration and tumor cell homing during metastasis. These results suggest that both PKC-ι and PKC-ζ are involved in signaling pathways which upregulate EMT and which can be effectively suppress using ICA-1 and Compound-50. Furthermore we established that treatment with ICA-1/Compound-50 induced apoptosis as shown by increasing Caspase-3 levels and decreasing Bcl-2 levels.

Citation Format: Wishrawana Sarathi Ratnayake, Mildred Acevedo-Duncan. Atypical protein kinase c inhibitors can repress epithelial to mesenchymal transition (type III) in malignant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 862. doi:10.1158/1538-7445.AM2017-862