Akademik Veri Yönetim Sistemi
OPHTHALMIC RESEARCH, sa.1, ss.1230-1244, 2023 (SCI-Expanded)
Introduction Uveal melanoma (UM) responds poorly to targeted therapies or immune-checkpoint inhibitors. AMP-activated protein kinase (AMPK) is a pivotal serine/threonine protein kinase that coordinates vital processes such as cell growth. Targeting AMPK pathway, which represents a critical mechanism mediating the survival of UM cells, may prove to be a novel treatment strategy for UM. We aimed to demonstrate the effects of AMPK modulation on UM cells. Methods In silico analyses were performed to compare UM and normal melanocyte cells via KEGG and GSEA. The effects of AMPK-modulation on cell viability and proliferation in UM cell lines with different molecular profiles (i.e., 92-1, MP46, OMM2.5 and Mel270) were investigated via XTT cell viability and proliferation assays after treating the cells with varying concentrations of A-769662 (AMPK-activator) or dorsomorphin (AMPK-inhibitor). Results KEGG/GSEA studies demonstrated that genes implicated in AMPK-signaling pathway were differentially regulated in UM. Gene-sets that comprise genes involved in AMPK-signaling and genes involved in energy-dependent-regulation of mTOR by LKB1-AMPK were downregulated in UM. We observed gradual decreases in the numbers of viable UM cells as the concentration of A-769662 treatment increased. All UM cells demonstrated statistically significant decreases in cell-viability, when treated with 200 mu M A-769662. Moreover, the effects of AMPK-inhibition on UM cells were potent, since low doses of dorsomorphin treatment resulted in significant decreases in viabilities of UM cells. The IC50 values proved the potency of dorsomorphin treatment against UM in vitro. Discussion/Conclusion AMPK may act like a friend or a foe in cancer depending on the context. As such, the current study contributes to the literature in determining the effects of therapeutic strategies targeting AMPK in several UM cells. We propose a new perspective in the treatment of UM. Targeting AMPK pathway may open up new avenues in developing novel therapeutic approaches to improve overall-survival in UM.