PI3K inhibition modulates PON gene expression and disrupts survival pathways in retinoblastoma Y-79 cells.
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BACKGROUND: Retinoblastoma is a pediatric intraocular cancer usually driven by RB1 gene mutations, with Y79 cells serving as a retinoblastoma model bearing RB1 inactivation. Paraoxonases (PON1, PON2, PON3) are antioxidant proteins; PON1 is HDL-associated, whereas PON2 and PON3 are intracellular, with PON2 localized to the inner mitochondrial membrane. The PI3K/Akt pathway is a key survival cascade frequently hyperactivated in cancer. This study evaluated PON isoform expression in Y79 retinoblastoma cells and examined whether their regulation is mediated by PI3K/Akt signaling. METHODS: Adult Retinal Pigment Epithelial (ARPE-19), Human Retinal Endothelial Cells (HREC), Human Retinal Pericytes (HRP), and Y79 cells were cultured under standard conditions, serum-starved, and treated with the Akt pathway inhibitor LY294002 (5 & 10 µM). Gene expression was assessed using quantitative real-time PCR. Protein expression of Akt, phosphorylated Akt (p-Akt), and PON2 was analyzed by Western blotting. Statistical analyses were performed using one-way ANOVA, and data were expressed as mean ± SEM. RESULTS: Our results showed that the expression of PON1 was increased; PON2 and PON3 were decreased in Y79 cells when compared with HREC, and ARPE-19. The expression of p-Akt was elevated in Y79 cells, and LY294002 decreased the expression of p-Akt and PON1 and PON3 without altering PON2 mRNA expression, indicating that there is differential regulation of PON genes in Y79 cells and is regulated by the PI3K/Akt pathway. CONCLUSION: These findings indicate that PI3K/Akt signaling sustains a pro-survival, antioxidant phenotype in retinoblastoma cells through selective regulation of PON isoforms, highlighting this pathway as a promising therapeutic target.