title: Reducing the serine availability complements the inhibition of the glutamine metabolism to block leukemia cell growth.
abstract: Leukemia cells are described as a prototype of glucose-consuming cells with a high turnover rate. The role of glutamine in fueling the tricarboxylic acid cycle of leukemia cells was however recently identified confirming its status of major anaplerotic precursor in solid tumors. Here we examined whether glutamine metabolism could represent a therapeutic target in leukemia cells and whether resistance to this strategy could arise. We found that glutamine deprivation inhibited leukemia cell growth but also led to a glucose-independent adaptation maintaining cell survival. A proteomic study revealed that glutamine withdrawal induced the upregulation of phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT), two enzymes of the serine pathway. We further documented that both exogenous and endogenous serine were critical for leukemia cell growth and contributed to cell regrowth following glutamine deprivation. Increase in oxidative stress upon inhibition of glutamine metabolism was identified as the trigger of the upregulation of PHGDH. Finally, we showed that PHGDH silencing in vitro and the use of serine-free diet in vivo inhibited leukemia cell growth, an effect further increased when glutamine metabolism was blocked. In conclusion, this study identified serine as a key pro-survival actor that needs to be handled to sensitize leukemia cells to glutamine-targeting modalities.
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Florence
authors.initials: F
authors.lastname: Polet
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Cyril
authors.initials: C
authors.lastname: Corbet
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Adan
authors.initials: A
authors.lastname: Pinto
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Laila Illan
authors.initials: LI
authors.lastname: Rubio
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Ruben
authors.initials: R
authors.lastname: Martherus
authors.affiliation: Pole of Medical Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Bol
authors.affiliation: Molecules, Solids and Reactivity (MOST), Institute of Condensed Matter and Nanosciences (IMCN), Université Catholique de Louvain, B-1348 Louvain-la-Neuve, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Drozak
authors.affiliation: Pole of Medical Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Grégoire
authors.affiliation: Molecules, Solids and Reactivity (MOST), Institute of Condensed Matter and Nanosciences (IMCN), Université Catholique de Louvain, B-1348 Louvain-la-Neuve, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Riant
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015180:Electrophoresis, Gel, Two-Dimensional; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D015151:Immunoblotting; D020014:K562 Cells; D053208:Kaplan-Meier Estimate; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D050543:Phosphoglycerate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D034622:RNA Interference; D012694:Serine / Q000378:metabolism*; D000637:Transaminases / Q000235:genetics / Q000378:metabolism
chemical_list: D005973:Glutamine; D012694:Serine; D050543:Phosphoglycerate Dehydrogenase; D000637:Transaminases; C022393:phosphoserine aminotransferase; D005947:Glucose
keywords: PHGDH; glutamine; leukemia; metabolism; serine