6-mercaptopurine promotes energetic failure in proliferating T cells

// Ana A. Fernández-Ramos 1, 2 , Catherine Marchetti-Laurent 1, 2 , Virginie Poindessous 1, 2 , Samantha Antonio 2, 3 , Pierre Laurent-Puig 1, 2, 4 , Sylvie Bortoli 2, 3 , Marie-Anne Loriot 1, 2, 4, * and Nicolas Pallet 1, 2, 4, * 1 INSERM UMR-S 1147, Centre Universitaire des Saints-Pères, 75006 Paris, France 2 Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France 3 INSERM UMR-S 1124, Centre Universitaire des Saints-Pères, 75006 Paris, France 4 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Biochimie, 75015 Paris, France * Co-senior authors Correspondence to: Marie-Anne Loriot, email: marie-anne.loriot@parisdescartes.fr Keywords: 6-mercaptopurine, energetic failure, metabolic checkpoints, acute lymphoblastic leukemia, Jurkat T cell line Received: December 15, 2016      Accepted: April 11, 2017      Published: May 16, 2017 ABSTRACT The anticancer drug 6-mercaptopurine (6-MP) inhibits de novo purine synthesis and acts as an antiproliferative agent by interfering with protein, DNA and RNA synthesis and promoting apoptosis. Metabolic reprogramming is crucial for tumor progression to foster cancer cells growth and proliferation, and is regulated by mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) as well as the oncogenes Myc and hypoxia inducible factor 1α (HIF-1α). We hypothesized that 6-MP impacts metabolic remodeling through its action on nucleotide synthesis. The aim of our study is to provide a comprehensive characterization of the metabolic changes induced by 6-MP in leukemic T cells. Our results indicate that exposition to 6-MP rapidly reduces intracellular ATP concentration, leading to the activation of AMPK. In turn, mTOR, an AMPK target, was inhibited, and the expression of HIF-1α and Myc was reduced upon 6-MP incubation. As a consequence of these inhibitions, glucose and glutamine fluxes were strongly decreased. Notably, no difference was observed on glucose uptake upon exposition to 6-MP. In conclusion, our findings provide new insights into how 6-MP profoundly impacts cellular energetic metabolism by reducing ATP production and decreasing glycolytic and glutaminolytic fluxes, and how 6-MP modifies human leukemic T cells metabolism with potential antiproliferative effects.