A novel inhibitor of the atypical protein kinase C-ι decreases the proliferation of malignant gastric cancer cells and disrupts the Skp-2 pathway

Global data on Gastric Cancer (GC) exhibit that it is the fifth most common type of cancer and as far as mortality is concerned, it is the third most common type. Late-stage diagnosis of GC is an important cause for high mortality. Even though Helicobacter pylori are known to be the most common cause of gastric cancer, other notable risk factors also include high salt intake, age and diets lacking in fruits and vegetables. Endoscopic resection is considered as the major treatment procedure for early detected gastric cancer while those diagnosed in later stages are treated with surgeries such as D2 lymphadenectomy. Previously, the Atypical Protein Kinase C Iota (PKC-ι) has been documented to play significant roles in elevated cell proliferation in various cancer types. Here, we employed a novel inhibitor, ICA-1S (5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide that specifically inhibits PKC-ι on a gastric cancer cell line (i.e., AGS) to observe its effects on cell proliferation. In separate trials, AGS cells were treated with ICA-1S for 96 hours (about 4 days). An assortment of drug concentrations for the inhibitor was tried and the analysis of the cell count demonstrated that the cell proliferation decreases were statistically significant. The highest decrease in cell proliferation was observed at 20 µM (p < 0.0001). Our previous research have revealed that this PKC inhibitor blocks PKC-ι and interferes with established cancer pathways to cause cell deaths. Based on that and the results from the preliminary data on this project, it can be hypothesized that this PKC inhibitor has the potential to lead to Gastric Cancer cell deaths by inducing apoptosis, which could potentially open a new door for Gastric Cancer therapeutics. Henceforth, the Western Blot analysis of AGS cells treated with ICA-1S has shown enhanced inhibition of PKC-ι, and increased apoptosis by the elevated cleavage of Caspase 3 and poly(ADP-ribose) polymerase (PARP). Moreover, we have seen an increased degradation in the S-phase kinase-associated protein 2 (Skp-2), an oncoprotein, suggesting that ICA-1S has the potential to be a drug candidate for the treatment of GC. Current investigations include examining how ICA-1S affects other proteins in the Skp-2 pathway to support our hypothesis that blocking PKC-ι disrupts the Skp-2 pathway, thereby killing GC cells.