A Purine Nucleotide Biosynthesis Enzyme Guanosine Monophosphate Reductase Is a Suppressor of Melanoma Invasion

• GMPR is downregulated in the invasive stages of cutaneous and metastatic melanoma
• GMPR inhibits invasion and tumorigenicity of melanoma cells
• GMPR suppresses activity of several Rho-GTPases
• Other enzymes of GTP biosynthesis regulate tumor cell invasion

SummaryMelanoma is one of the most aggressive types of human cancers, and the mechanisms underlying melanoma invasive phenotype are not completely understood. Here, we report that expression of guanosine monophosphate reductase (GMPR), an enzyme involved in de novo biosynthesis of purine nucleotides, was downregulated in the invasive stages of human melanoma. Loss- and gain-of-function experiments revealed that GMPR downregulates the amounts of several GTP-bound (active) Rho-GTPases and suppresses the ability of melanoma cells to form invadopodia, degrade extracellular matrix, invade in vitro, and grow as tumor xenografts in vivo. Mechanistically, we demonstrated that GMPR partially depletes intracellular GTP pools. Pharmacological inhibition of de novo GTP biosynthesis suppressed whereas addition of exogenous guanosine increased invasion of melanoma cells as well as cells from other cancer types. Our data identify GMPR as a melanoma invasion suppressor and establish a link between guanosine metabolism and Rho-GTPase-dependent melanoma cell invasion.

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