Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target.
The importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell lines (HMCLs) are highly sensitive to Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) CD138(+) cells produced large amounts of ammonium in the presence of Gln. MM patients have lower BM plasma Gln with higher ammonium and glutamate than patients with indolent monoclonal gammopathies. Interestingly, HMCLs expressed glutaminase (GLS1) and were sensitive to its inhibition, whereas they exhibited negligible expression of glutamine synthetase (GS). High GLS1 and low GS expression were also observed in primary CD138(+) cells. Gln-free incubation or treatment with the glutaminolytic enzyme l-asparaginase depleted the cell contents of Gln, glutamate, and the anaplerotic substrate 2-oxoglutarate, inhibiting MM cell growth. Consistent with the dependence of MM cells on extracellular Gln, a gene expression profile analysis, on both proprietary and published datasets, showed an increased expression of the Gln transporters SNAT1, ASCT2, and LAT1 by CD138(+) cells across the progression of monoclonal gammopathies. Among these transporters, only ASCT2 inhibition in HMCLs caused a marked decrease in Gln uptake and a significant fall in cell growth. Consistently, stable ASCT2 downregulation by a lentiviral approach inhibited HMCL growth in vitro and in a murine model. In conclusion, MM cells strictly depend on extracellular Gln and show features of Gln addiction. Therefore, the inhibition of Gln uptake is a new attractive therapeutic strategy for MM.
Myeloma Unit, Department of Clinical and Experimental Medicine, and.
Marina
0000-0002-0821-8093
M
Bolzoni
Unit of General Pathology, Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Parma, Italy;
Martina
0000-0002-5655-9984
M
Chiu
Myeloma Unit, Department of Clinical and Experimental Medicine, and Hematology and BMT Center, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy;
Fabrizio
F
Accardi
Myeloma Unit, Department of Clinical and Experimental Medicine, and.
Rosanna
R
Vescovini
Laboratorio di Oncologia, Istituto Giannina Gaslini, Genoa, Italy;
Irma
I
Airoldi
Myeloma Unit, Department of Clinical and Experimental Medicine, and CoreLab, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy;
Paola
P
Storti
Laboratory of Pre-clinical and Translational Research, Istituto di Ricovero e Cura a Carattere Scientifico, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy;
Katia
K
Todoerti
Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy;
Luca
L
Agnelli
Infectious Disease Unit and Hepatology Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy;
Gabriele
G
Missale
Unit of Occupational Medicine, Department of Clinical and Experimental Medicine, and.
Roberta
R
Andreoli
Unit of General Pathology, Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Parma, Italy; Unit of Occupational Medicine, Department of Clinical and Experimental Medicine, and.
Massimiliano G
0000-0002-4179-6573
MG
Bianchi
Unit of General Pathology, Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Parma, Italy;
Manfredi
M
Allegri
Unit of General Pathology, Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Parma, Italy;
Amelia
A
Barilli
Cardiac Surgery Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy;
Francesco
F
Nicolini
Infectious Disease Unit and Hepatology Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy;
Albertina
A
Cavalli
Myeloma Unit, Department of Clinical and Experimental Medicine, and.
Federica
F
Costa
Myeloma Unit, Department of Clinical and Experimental Medicine, and CoreLab, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy;
Valentina
V
Marchica
Myeloma Unit, Department of Clinical and Experimental Medicine, and.
Denise
D
Toscani
U.O. di Anatomia Patologica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; and.
Cristina
C
Mancini
U.O. di Anatomia Patologica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; and.
Eugenia
E
Martella
Unit of General Pathology, Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Parma, Italy;
Valeria
V
Dall'Asta
Department of Medical-Veterinary Science, University of Parma, Parma, Italy.
Gaetano
G
Donofrio
Myeloma Unit, Department of Clinical and Experimental Medicine, and Hematology and BMT Center, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy;
Franco
F
Aversa
Unit of General Pathology, Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Parma, Italy;
Ovidio
0000-0002-4301-2939
O
Bussolati
Myeloma Unit, Department of Clinical and Experimental Medicine, and Hematology and BMT Center, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; CoreLab, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy;
Nicola
0000-0003-3457-3774
N
Giuliani
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D026962:Amino Acid Transport System ASC / Q000378:metabolism; D064751:Ammonium Compounds / Q000378:metabolism; D000818:Animals; D001215:Asparaginase / Q000378:metabolism; D001692:Biological Transport; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D005972:Glutaminase / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D058990:Molecular Targeted Therapy; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000473:pathology; D009101:Multiple Myeloma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053668:Syndecan-1 / Q000378:metabolism
D026962:Amino Acid Transport System ASC; D064751:Ammonium Compounds; D026901:Membrane Transport Proteins; D015778:Minor Histocompatibility Antigens; C420506:SLC1A5 protein, human; D053668:Syndecan-1; D005973:Glutamine; D001215:Asparaginase; D005972:Glutaminase; D005974:Glutamate-Ammonia Ligase