Therapeutic potential of a selective protein kinase Ciota inhibitor, in suppressing PI3K/AKT driven pancreatic ductal adenocarcinoma proliferation

Pancreatic cancer remains one of the most lethal malignancies due to its late-stage diagnosis and pronounced chemoresistance, ranking as the third leading cause of cancer-related deaths in the United States. Atypical Protein Kinase C (aPKC) isoforms, Protein Kinase C-iota (PKC-ι) and Protein Kinase C- zeta (PKC-ζ), are critical regulators of oncogenic signaling pathways that drive cancer cell proliferation, metastasis, and survival. In this study, we investigated the therapeutic potential of ICA-1S [5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide], a selective PKC-ι inhibitor, in pancreatic adenocarcinoma cell lines AsPC1 and PANC1. Dose-response analyses revealed maximal inhibitory effects at 10 μM ICA-1S, reducing cell proliferation by 52% in AsPC1 and 49.8% in PANC1 cells. Western blot analysis performed on AsPC1 cell line confirmed downregulation of PKC-ι and PKC-ζ protein expression following treatment. Mechanistic studies demonstrated that ICA-1S (10 μM) significantly attenuated the Phosphatidylinositol 3-Kinase (PI3K)/Protein Kinase B (AKT) signaling cascade, phosphorylated Phosphatidylinositol 3-Kinase (pPI3K) by 51%, and total PI3K by 18%. This suppression led to a 39% decrease in phosphorylated AKT (pAKT) and an 18% decrease in total AKT, demonstrating inhibition of downstream PI3K pathway signaling. Additionally, ICA-1S treatment induced apoptosis in AsPC1 cells, as evidenced by increased expression of Cleaved Caspase-9 by 10%, increased Cytochrome c release by 17%, and decreased expression of the anti-apoptotic protein Survivin by 42%. Wound-healing assays further demonstrated the anti-metastatic effect of ICA-1S, with treated AsPC1 cells failing to close wounds even after five days, while control cells achieved complete closure.Collectively, these findings indicate that ICA-1S effectively suppresses PKC-ι-mediated PI3K/AKT signaling and promotes apoptosis in pancreatic cancer cells, underscoring its potential as a promising targeted therapeutic agent for pancreatic adenocarcinoma. Ongoing studies will employ Water-Soluble Tetrazolium (WST) assays, immunoprecipitation, immunofluorescence, and extended Western blot analyses to further delineate the downstream molecular effects of ICA-1S.