Regulation of the proapoptotic functions of prostate apoptosis response-4 (Par-4) by casein kinase 2 in prostate cancer cells

de Thonel A, A Hazoumé, Vitaly Kochin, Kimmo Isoniemi, G Jego, E Fourmaux, A Hammann, H Mjahed, O Filhol, O Micheau, P Rocchi, V Mezger, John Eriksson, VM Rangnekar, C Garrido

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    10 Sitaatiot (Scopus)

    Abstrakti

    The proapoptotic protein, prostate apoptosis response-4 (Par-4), acts as a tumor suppressor in prostate cancer cells. The serine/threonine kinase casein kinase 2 (CK2) has a well-reported role in prostate cancer resistance to apoptotic agents or anticancer drugs. However, the mechanistic understanding on how CK2 supports survival is far from complete. In this work, we demonstrate both in rat and humans that (i) Par-4 is a new substrate of the survival kinase CK2 and (ii) phosphorylation by CK2 impairs Par-4 proapoptotic functions. We also unravel different levels of CK2-dependent regulation of Par-4 between species. In rats, the phosphorylation by CK2 at the major site, S124, prevents caspase-mediated Par-4 cleavage (D123) and consequently impairs the proapoptotic function of Par-4. In humans, CK2 strongly impairs the apoptotic properties of Par-4, independently of the caspase-mediated cleavage of Par-4 (D131), by triggering the phosphorylation at residue S231. Furthermore, we show that human Par-4 residue S231 is highly phosphorylated in prostate cancer cells as compared with their normal counterparts. Finally, the sensitivity of prostate cancer cells to apoptosis by CK2 knockdown is significantly reversed by parallel knockdown of Par-4. Thus, Par-4 seems a critical target of CK2 that could be exploited for the development of new anticancer drugs.
    AlkuperäiskieliEi tiedossa
    Sivut1–13
    JulkaisuCell Death and Disease
    Vuosikerta5
    DOI - pysyväislinkit
    TilaJulkaistu - 2014
    OKM-julkaisutyyppiA1 Julkaistu artikkeli, soviteltu

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