ICA-1S targets PKC-ι and Cx43 to inhibit glioblastoma multiforme progression

Glioblastoma multiforme (GBM) is an aggressive brain cancer, characterized by poor therapeutic outcomes. Atypical protein kinase C iota (PKC-ι) plays a critical role in GBM progression by regulating cell proliferation, motility, and invasion. Connexin 43 (Cx43), a key gap junction protein, mediates intercellular communication between glioma and surrounding astrocytes, promoting tumor growth, invasion, and chemoresistance. Targeting the PKC-ι and Cx43 represents a novel approach to disrupt oncogenic interactions and inhibit GBM progression. This study evaluates the therapeutic potential of ICA-1S ((-Amino-1-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(phosphonooxy)methyl]cyclopentyl]-1H-imidazole-4-carboxamide), a selective PKC-ι inhibitor, on GBM cell proliferation, signaling, and Cx43 regulation. Treatment of T98G and U87MG cells with ICA-1S resulted in significant reductions in cell proliferation by about 50% in T98G and 40% in U87MG (p < 0.001). Co-immunoprecipitation experiments demonstrated that PKC-ι directly interacts with Cx43. Treatment with ICA-1S led to decreased expression of both PKC-ι and Cx43, as shown by Western blot analysis. In addition, ICA-1S promoted autophagy and inhibited critical oncogenic signaling pathways, including PI3K/AKT, while also reducing the expression of proteins involved in epithelial-mesenchymal transition. These results indicate that ICA-1S is a promising candidate for targeted GBM therapy.