title: A purine nucleotide biosynthesis enzyme guanosine monophosphate reductase is a suppressor of melanoma invasion.
abstract: Melanoma 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.
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Wawrzyniak
authors.forename: Anna
authors.initials: A
authors.lastname: Bianchi-Smiraglia
authors.forename: Wiam
authors.initials: W
authors.lastname: Bshara
authors.forename: Sudha
authors.initials: S
authors.lastname: Mannava
authors.forename: Jeff
authors.initials: J
authors.lastname: Ackroyd
authors.forename: Archis
authors.initials: A
authors.lastname: Bagati
authors.forename: Angela R
authors.initials: AR
authors.lastname: Omilian
authors.forename: Michael
authors.initials: M
authors.lastname: Im
authors.forename: Natalia
authors.initials: N
authors.lastname: Fedtsova
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Miecznikowski
authors.forename: Kalyana C
authors.initials: KC
authors.lastname: Moparthy
authors.forename: Shoshanna N
authors.initials: SN
authors.lastname: Zucker
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Zhu
authors.forename: Nadezhda I
authors.initials: NI
authors.lastname: Kozlova
authors.forename: Albert E
authors.initials: AE
authors.lastname: Berman
authors.forename: Keith S
authors.initials: KS
authors.lastname: Hoek
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
authors.forename: Donna S
authors.initials: DS
authors.lastname: Shewach
authors.forename: Carl D
authors.initials: CD
authors.lastname: Morrison
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Nikiforov
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D005109:Extracellular Matrix / Q000378:metabolism; D050899:GMP Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D007168:IMP Dehydrogenase / Q000378:metabolism; D008545:Melanoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010641:Phenotype; D011684:Purine Nucleosides / Q000096:biosynthesis*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014183:Transplantation, Heterologous; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D011684:Purine Nucleosides; D034741:RNA, Small Interfering; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; C501687:IMPDH2 protein, human; D050899:GMP Reductase; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins