TY - JOUR
T1 - A Purine Nucleotide Biosynthesis Enzyme Guanosine Monophosphate Reductase Is a Suppressor of Melanoma Invasion
AU - Wawrzyniak, Joseph A.
AU - Bianchi-Smiraglia, Anna
AU - Bshara, Wiam
AU - Mannava, Sudha
AU - Ackroyd, Jeff
AU - Bagati, Archis
AU - Omilian, Angela R.
AU - Im, Michael
AU - Fedtsova, Natalia
AU - Miecznikowski, Jeffrey C.
AU - Moparthy, Kalyana C.
AU - Zucker, Shoshanna N.
AU - Zhu, Qianqian
AU - Kozlova, Nadezhda I.
AU - Berman, Albert E.
AU - Hoek, Keith S.
AU - Gudkov, Andrei V.
AU - Shewach, Donna S.
AU - Morrison, Carl D.
AU - Nikiforov, Mikhail A.
PY - 2013
Y1 - 2013
N2 - 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 invitro, and grow as tumor xenografts invivo. 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
AB - 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 invitro, and grow as tumor xenografts invivo. 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
UR - https://www.scopus.com/pages/publications/84887023562
U2 - 10.1016/j.celrep.2013.09.015
DO - 10.1016/j.celrep.2013.09.015
M3 - Article
C2 - 24139804
AN - SCOPUS:84887023562
SN - 2639-1856
VL - 5
SP - 493
EP - 507
JO - Cell Reports
JF - Cell Reports
IS - 2
ER -