PMID- 28574837
OWN - NLM
STAT- MEDLINE
DCOM- 20180406
LR  - 20181113
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 8
IP  - 26
DP  - 2017 Jun 27
TI  - 6-mercaptopurine promotes energetic failure in proliferating T cells.
PG  - 43048-43060
LID - 10.18632/oncotarget.17889 [doi]
AB  - 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 1alpha (HIF-1alpha). 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-1alpha 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.
FAU - Fernandez-Ramos, Ana A
AU  - Fernandez-Ramos AA
AD  - INSERM UMR-S 1147, Centre Universitaire des Saints-Peres, 75006 Paris, France.
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Marchetti-Laurent, Catherine
AU  - Marchetti-Laurent C
AD  - INSERM UMR-S 1147, Centre Universitaire des Saints-Peres, 75006 Paris, France.
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Poindessous, Virginie
AU  - Poindessous V
AD  - INSERM UMR-S 1147, Centre Universitaire des Saints-Peres, 75006 Paris, France.
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Antonio, Samantha
AU  - Antonio S
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
AD  - INSERM UMR-S 1124, Centre Universitaire des Saints-Peres, 75006 Paris, France.
FAU - Laurent-Puig, Pierre
AU  - Laurent-Puig P
AD  - INSERM UMR-S 1147, Centre Universitaire des Saints-Peres, 75006 Paris, France.
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
AD  - Assistance Publique-Hopitaux de Paris, Hopital Europeen Georges Pompidou, Service 
      de Biochimie, 75015 Paris, France.
FAU - Bortoli, Sylvie
AU  - Bortoli S
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
AD  - INSERM UMR-S 1124, Centre Universitaire des Saints-Peres, 75006 Paris, France.
FAU - Loriot, Marie-Anne
AU  - Loriot MA
AD  - INSERM UMR-S 1147, Centre Universitaire des Saints-Peres, 75006 Paris, France.
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
AD  - Assistance Publique-Hopitaux de Paris, Hopital Europeen Georges Pompidou, Service 
      de Biochimie, 75015 Paris, France.
FAU - Pallet, Nicolas
AU  - Pallet N
AD  - INSERM UMR-S 1147, Centre Universitaire des Saints-Peres, 75006 Paris, France.
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
AD  - Assistance Publique-Hopitaux de Paris, Hopital Europeen Georges Pompidou, Service 
      de Biochimie, 75015 Paris, France.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 415SHH325A (Adenosine Monophosphate)
RN  - 61D2G4IYVH (Adenosine Diphosphate)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - E7WED276I5 (Mercaptopurine)
SB  - IM
MH  - Adenosine Diphosphate/metabolism
MH  - Adenosine Monophosphate/metabolism
MH  - Adenosine Triphosphate/metabolism
MH  - Antimetabolites, Antineoplastic/*pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Cycle Checkpoints/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Energy Metabolism/*drug effects
MH  - Glycolysis/drug effects
MH  - Humans
MH  - Lymphocyte Activation/drug effects/immunology
MH  - Mercaptopurine/*pharmacology
MH  - Metabolic Networks and Pathways/drug effects
MH  - Stress, Physiological/drug effects
MH  - T-Lymphocytes/*drug effects/*physiology
PMC - PMC5522126
OTO - NOTNLM
OT  - 6-mercaptopurine
OT  - Jurkat T cell line
OT  - acute lymphoblastic leukemia
OT  - energetic failure
OT  - metabolic checkpoints
COIS- CONFLICTS OF INTEREST The authors declare that they have no competing interests.
EDAT- 2017/06/03 06:00
MHDA- 2018/04/07 06:00
PMCR- 2017/06/27
CRDT- 2017/06/03 06:00
PHST- 2016/12/15 00:00 [received]
PHST- 2017/04/11 00:00 [accepted]
PHST- 2017/06/03 06:00 [pubmed]
PHST- 2018/04/07 06:00 [medline]
PHST- 2017/06/03 06:00 [entrez]
PHST- 2017/06/27 00:00 [pmc-release]
AID - 17889 [pii]
AID - 10.18632/oncotarget.17889 [doi]
PST - ppublish
SO  - Oncotarget. 2017 Jun 27;8(26):43048-43060. doi: 10.18632/oncotarget.17889.