Adenosine kinase role in melanoma progression and resistance
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Background Adenosine kinase (ADK) regulates adenosine (ADO) metabolism, influencing cellular homeostasis, proliferation, and epigenetic regulation. In cancer, ADK is linked to immunosuppression and inflammation, but its role in melanoma remains unclear. Previous studies suggest altered ADK expression during melanoma progression, implicating it in tumor development, differentiation, and therapy resistance. Given ADO’s role in modulating the tumor microenvironment, targeting ADK may provide insights into melanoma progression and treatment resistance. This study investigates ADK’s role in melanoma development and resistance mechanisms, exploring its potential as a therapeutic target or prognostic marker. Methods ADK expression was analyzed in melanoma cell lines with varying resistance profiles and BRAF/NRAS mutation backgrounds. Pharmacological ADK inhibition (ADKi, using ABT-702) was assessed for effects on proliferation, colony formation, invasion, apoptosis, and cell cycle. Gene expression profiling identified molecular signatures associated with ADK modulation. Results ADK was downregulated in BRAF inhibitor (BRAFi)-resistant cells compared to parental lines, with nuclear localization suggesting ADK-L isoform dominance. ADKi reduced colony formation and proliferation in a dose- and resistance-dependent manner. While it decreased invasion in parental cells, no effect was observed in resistant lines. ADKi also modulated viability and apoptosis in parental cells but had no impact on resistant cells or cell cycle progression. Gene expression analysis revealed alterations in oncogenic pathways (e.g., cathepsins, protein kinases) linked to tumor progression and resistance. Conclusion ADK expression changes during melanoma progression and resistance development, but its downregulation appears to be a consequence rather than a driver of resistance. Further genomic and molecular studies are needed to elucidate the role of ADK in melanoma progression and treatment strategies.
