Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

Abstract

Malignant melanoma possesses one of the highest metastatic potentials among human cancers. Acquisition of invasive phenotypes is a prerequisite for melanoma metastases. Elucidation of the molecular mechanisms underlying melanoma invasion will greatly enhance the design of novel agents for melanoma therapeutic intervention. Here, we report that guanosine monophosphate synthase (GMPS), an enzyme required for the de novo biosynthesis of GMP, has a major role in invasion and tumorigenicity of cells derived from either BRAF V600E or NRAS Q61R human metastatic melanomas. Moreover, GMPS levels are increased in metastatic human melanoma specimens compared with primary melanomas arguing that GMPS is an attractive candidate for anti-melanoma therapy. Accordingly, for the first time we demonstrate that angustmycin A, a nucleoside-analog inhibitor of GMPS produced by Streptomyces hygroscopius efficiently suppresses melanoma cell invasion in vitro and tumorigenicity in immunocompromised mice. Our data identify GMPS as a powerful driver of melanoma cell invasion and warrant further investigation of angustmycin A as a novel anti-melanoma agent.

Microphthalmia-associated transcription factor suppresses invasion by reducing intracellular GTP pools

“…The important role of several de novo guanylate metabolism enzymes, including GMPR and its functional antagonists IMPDH2 and GMPS in regulation of RHO-GTPases activity and/or tumor cell invasion has been described by us and others (8–12, 45). The current paper demonstrates that transactivation of GMPR mediates the ability of MITF to suppress invasion, tumorigenicity and metastasis in melanoma cells, thus connecting this important transcription factor with regulation of guanylate metabolism (Fig.…”

“…Our recent studies have established that in tumor cells, including melanoma, invasion is regulated by several enzymes involved in the guanylate metabolism pathway (8, 9). This regulation occurs through modulation of intracellular GTP pools, which affects the activity of several members of RHO-GTPase family (9–11).…”

Slowing down the Grand Touring Prototype speed of cancer cells

“…Importantly, levels of enzymes regulating nucleotide metabolism, including metabolism of guanylates are often changed in human cancers. 1–5 …”

“…In our current work, we identified GMP synthase (GMPS, another key enzyme in guanylate metabolism and a functional antagonist of GMPR (Figure 1)) as a driver of melanoma invasion. 1 …”

“…One such example is our current finding that Angustmycin A, a potent antibiotic produced by fungi Streptomyces hygroscopius and a selective inhibitor of GMPS, reduces the invasion of metastatic melanoma cells in vitro and their growth as xenografts in vivo . 1 …”