Abstract 4383: Atypical protein kinases C-ζ and ι-inhibitors impede the growth of malignant gastric cancer cells

Abstract

Abstract Currently, the global data on gastric cancer demonstrate that it is the fifth most common type of cancer and as far as cancer-related death is concerned, it is the third most common type. The high mortality of gastric cancer can be attributed to the fact that it is mostly diagnosed when the disease has progressed to the advanced stage. While the bacterium Helicobacter pylori is 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. Demographic data have revealed that the regions of East Asia, Eastern Europe and South America are notable hotspots of this type of cancer. 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 Kinases C (aPKCs) - ζ and ι - have been documented to play significant roles in elevated cell proliferation in various cancer types. Here, we employed two inhibitors, ICA-1S (5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide and ζ-stat (8-hydroxy-1,3,6- naphthalenetrisulfonic acid), that specifically inhibit aPKC-ι and-ζ respectively on a gastric cancer cell line (i.e., AGS) to observe their effects on cell proliferation. In separate trials, AGS cells were treated with ICA-1S and ζ-stat for 72 hours (about 3 days). An assortment of drug concentrations for each of the inhibitors were tried and the analysis of the cell count demonstrated that the cell proliferation decreases were statistically significant for both drugs in all concentrations. In case of ICA-1S, the highest decrease in cell proliferation was observed at 20 µM (p < 0.0001), whereas in case of ζ-stat, the highest decrease was observed at 10 µM (p < 0.0001). Our previous research have revealed that these aPKC inhibitors downregulate the aPKCs-ι and-ζ and interfere 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 these two aPKC inhibitors have the potential to lead to Gastric Cancer cell deaths, which could potentially open a new door for Gastric Cancer therapeutics. Henceforth, the Western Blot analysis of AGS cells treated with ζ-stat have demonstrated the downregulation of the aPKC-ζ protein. Likewise, a downregulation of the apoptosis-related markers, Survivin and Caspase-3, was also illustrated in ζ-stat treated cells. Current, investigations include how these aPKC inhibitors, ICA-1S and ζ-stat, play into some of the well-established gastric cancer pathways to lead to cell deaths with techniques such as Western Blot analysis, Immunoprecipitation Assays and Flow cytometry. Citation Format: Abiral Hasib Shourav, Mahfuza Marzan, Khandker Mohammad Khalid, Wishrawana Sarathi Ratnayake, Mildred Acevedo-Duncan. Atypical protein kinases C-ζ and ι-inhibitors impede the growth of malignant gastric cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4383.