title: 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.
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bianchi-Smiraglia
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Wawrzyniak
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bagati
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: E K
authors.initials: EK
authors.lastname: Marvin
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ackroyd
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: S
authors.initials: S
authors.lastname: Moparthy
authors.affiliation: Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: W
authors.initials: W
authors.lastname: Bshara
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Fink
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Foley
authors.affiliation: Orekhovich Institute of Biomedical Chemistry, Moscow 119121, Russia.
authors.forename: G E
authors.initials: GE
authors.lastname: Morozevich
authors.affiliation: Orekhovich Institute of Biomedical Chemistry, Moscow 119121, Russia.
authors.forename: A E
authors.initials: AE
authors.lastname: Berman
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Shewach
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Nikiforov
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006157:Guanosine Monophosphate / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms; D000096142:Cutaneous Malignant Melanoma
chemical_list: D004791:Enzyme Inhibitors; C012182:angustmycin A; D006157:Guanosine Monophosphate; D009713:Nucleotidyltransferases; D000241:Adenosine