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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.
AuthorsA Bianchi-Smiraglia, J A Wawrzyniak, A Bagati, E K Marvin, J Ackroyd, S Moparthy, W Bshara, E E Fink, C E Foley, G E Morozevich, A E Berman, D S Shewach, M A Nikiforov
JournalCell death and differentiation (Cell Death Differ) Vol. 22 Issue 11 Pg. 1858-64 (Nov 2015) ISSN: 1476-5403 [Electronic] England
PMID25909885 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Enzyme Inhibitors
  • angustmycin A
  • Guanosine Monophosphate
  • Nucleotidyltransferases
  • Adenosine
Topics
  • Adenosine (analogs & derivatives, pharmacology)
  • Animals
  • Cell Line, Tumor
  • Enzyme Inhibitors (pharmacology)
  • Female
  • Guanosine Monophosphate (metabolism)
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Melanoma (enzymology, pathology)
  • Mice
  • Mice, SCID
  • Nucleotidyltransferases (antagonists & inhibitors, genetics, metabolism)
  • Skin Neoplasms

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