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Sci Rep. 2016 Oct 19;6:35561. doi: 10.1038/srep35561.

Cytoplasmic proliferating cell nuclear antigen connects glycolysis and cell survival in acute myeloid leukemia.

Ohayon D1,2,3,4, De Chiara A1,2,3,4, Chapuis N1,2,3,5,6, Candalh C1,2,3,4, Mocek J1,2,3,4, Ribeil JA2,7, Haddaoui L1,2,3,6, Ifrah N6,8, Hermine O2,9,10, Bouillaud F1,2,3, Frachet P11,12, Bouscary D1,2,3,5,6, Witko-Sarsat V1,2,3,4.

Author information

1
INSERM U1016, Institut Cochin, Paris, France.
2
Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France.
3
CNRS UMR 8104, Paris, France.
4
Center of Excellence, Labex Inflamex, France.
5
Hematology Department, Cochin Hospital, Assistance publique-Hôpitaux de Paris (APHP), Paris, France.
6
FILO: French Innovative Leukemia Organization (GOELAMS), CHU Bretonneau, TOURS France.
7
Biotherapy Department, Necker Hospital, Paris, France.
8
Hematology Department CHU &UMR INSERM U892/CNRS6299, Université d'Angers, France.
9
Hematology Department, Necker Hospital Assistance publique-Hôpitaux de Paris (APHP), France.
10
INSERM UMR1163, CNRS ERL 8254, Institut Imagine, Paris, France.
11
Institut de Biologie Structurale, Centre Etude Atomique, Grenoble, France.
12
Université Grenoble Alpes, CNRS, UMR 5075, Grenoble, France.

Abstract

Cytosolic proliferating cell nuclear antigen (PCNA), a scaffolding protein involved in DNA replication, has been described as a key element in survival of mature neutrophil granulocytes, which are non-proliferating cells. Herein, we demonstrated an active export of PCNA involved in cell survival and chemotherapy resistance. Notably, daunorubicin-resistant HL-60 cells (HL-60R) have a prominent cytosolic PCNA localization due to increased nuclear export compared to daunorubicin-sensitive HL-60 cells (HL-60S). By interacting with nicotinamide phosphoribosyltransferase (NAMPT), a protein involved in NAD biosynthesis, PCNA coordinates glycolysis and survival, especially in HL-60R cells. These cells showed a dramatic increase in intracellular NAD+ concentration as well as glycolysis including increased expression and activity of hexokinase 1 and increased lactate production. Furthermore, this functional activity of cytoplasmic PCNA was also demonstrated in patients with acute myeloid leukemia (AML). Our data uncover a novel pathway of nuclear export of PCNA that drives cell survival by increasing metabolism flux.

PMID:
27759041
PMCID:
PMC5069676
DOI:
10.1038/srep35561
[Indexed for MEDLINE]
Free PMC Article

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