Reducing the serine availability complements the inhibition of the glutamine metabolism to block leukemia cell growth
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Florence Polet1, Cyril Corbet1, Adan Pinto1, Laila Illan Rubio1, Ruben Martherus1, Vanesa Bol2, Xavier Drozak3, Vincent Grégoire2, Olivier Riant3, Olivier Feron1
1Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, B-1200 Brussels, Belgium
2Pole of Medical Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, B-1200 Brussels, Belgium
3Molecules, Solids and Reactivity (MOST), Institute of Condensed Matter and Nanosciences (IMCN), Université catholique de Louvain, B-1348 Louvain-la-Neuve, Belgium
Olivier Feron, e-mail: firstname.lastname@example.org
Keywords: glutamine, serine, PHGDH, metabolism, leukemia
Received: August 17, 2015 Accepted: November 16, 2015 Published: November 28, 2015
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.
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