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    When PCNA migrates, cancer cells feast

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    Teams "Neutrophils and vasculitis" & "Normal and pathological hematopoiesis"

    W-S.V_FigureA-pcna_dna_tricolor

    Researchers have discovered that PCNA, a protein important in DNA replication and repair, can migrated from its normal nuclear location into the cytoplast during acute myeloid leukemia. 

    This new location can in turn "feed" cancer cells with glucose, ensuring their survival.

     

    Do you know the "maestro of replication"?

    W-S.V_CélineRichard_PFImagICW-S.V_CelineRichard_PFImagICThis is what researchers call PCNA (proliferating cell nuclear antigen), a protein with a very specific role in the nucleus of cells: by associating itself with other molecules, it co-ordinates the replication and repair of DNA.   A team of Parisian researchers including Véronique Witko-Sarsat, Didier Bouscary and Olivier Hermine found that at the time of diagnosis, half of patients with acute myeloid leukemia (AML) have an abnormal localization of PCNA in the cytoplasm. "We knew from previous research done on neutrophils - a type of white blood cells - that the fact that PCNA is located in the cytoplasm plays a role in cell survival, in general. The serious proportion - 50% of patients with AML with this PCNA cytoplasmic localization - observed at diagnosis suggests that this is an important mechanism and sufficiently ubiquitous to promote the survival of leukemia cells, "explains Véronique Witko-Sarsat.

    In particular, the researchers found that PCNA was located within the cytoplasm in a leukemic cell lines which is resistant to daunorubicin, a major drug used in AML chemotherapy. They have also identified one of the mechanisms that allow these leukemic cells to survive; through its association with glycolytic enzymes, cytoplasmic PCNA controls glucose metabolism, called glycolysis, which provides energy to the cell. "Chemotherapy-resistant leukemic cells with cytoplasmic PCNA have abnormally high glycolysis. The energy produced by this "unleashed" glycolysis is used to stimulate, even more, the active export of PCNA from the nucleus to the cytoplasm", describes the researcher. Therapeutic options are currently lacking to treat AML. "The main treatment, which combines daunorubicin and aracytin, attacks the consequence of the disease, that is, the proliferation of cells. As a result, it kills dividing cells, and especially cancer cells. Except that there are many healthy cells that divide in our body which will unfortunately also be destroyed by this treatment. The consequences are heavy for patients" says Véronique Witko-Sarsat. The original mechanisms discovered by the researcher and her collaborators open up new therapeutic perspectives. The involvement of PCNA in glycolysis could for example allow the development of treatments that directly target cytoplasmic PCNAs, such as peptides or small molecules already patented, and in turn cut one of the means by which the leukemic cells assure their survival.

     

    Publication:

    Ohayon D, De Chiara A, Chapuis N, Candalh C, Mocek J, Ribeil JA, Haddaoui L, Ifrah N, Hermine O, Bouillaud F, Frachet P, Bouscary D, Witko-Sarsat V.
    Cytoplasmic proliferating cell nuclear antigen connects glycolysis and cell survival in acute myeloid leukemia.
    Sci Rep. 2016 Oct 19;6:35561.

     

    Contact Institut Cochin:

    Véronique Witko-Sarsat: Didier Bouscary:

     

    Figure legends:
    During DNA replication, PCNA is a trimeric protein inside which the DNA double helix can insert (Molecular modeling figure).
    It is shown that in the HL60 cells sensitive to chemotherapy (left), PCNA (labelled in red) is located within the nucleus (in blue). In the resistant cells (right), PCNA is mainly cytoplasmic (immunofluorescence photo).