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

A. de Thonel; A. Hazoumé; V. Kochin; K. Isoniemi; G. Jego; E. Fourmaux; A. Hammann; H. Mjahed; O. Filhol; O. Micheau; P. Rocchi; V. Mezger; J. E. Eriksson; V. M. Rangnekar; C. Garrido

doi:10.1038/cddis.2013.532

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

A. de Thonel, A. Hazoumé, V. Kochin, K. Isoniemi, G. Jego, E. Fourmaux, A. Hammann, H. Mjahed, O. Filhol, O. Micheau, P. Rocchi, V. Mezger, J. E. Eriksson, V. M. Rangnekar, C. Garrido

Markey Cancer Center / Cancer Research Priority Initiative

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

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.

Original language	English
Journal	Cell Death and Disease
Volume	5
DOIs	https://doi.org/10.1038/cddis.2013.532
State	Published - 2014

Bibliographical note

Funding Information:
Acknowledgements. We thank Professor Sistonen (Turku Centre of Biotechnology, Finland), Dr. Downward (London Research institute, England), Dr. Robert (University of Manchester, England) for plasmid gifts, and Professor Schneider (University of Lausanne, Switzerland) for recombinant TRAIL. This work was supported by grants from the ‘Ligue Nationale Contre le Cancer’ and its committees in ‘Nièvre‘and ‘Sâone et Loire’ and in part by funding from the NCI/NIH (grant CA60872 to VMR) AH is recipient of a post-doctoral fellowship from the ‘Conseil regional de Bourgogne’, AdT has a post-doctoral fellowship from the ‘Association pour la Recherche contre le Cancer’. CG’s team has the ‘Label’ from the ‘Ligue Nationale contre le Cancer’.

ASJC Scopus subject areas

Immunology
Cellular and Molecular Neuroscience
Cell Biology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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de Thonel, A., Hazoumé, A., Kochin, V., Isoniemi, K., Jego, G., Fourmaux, E., Hammann, A., Mjahed, H., Filhol, O., Micheau, O., Rocchi, P., Mezger, V., Eriksson, J. E., Rangnekar, V. M., & Garrido, C. (2014). Regulation of the proapoptotic functions of prostate apoptosis response-4 (Par-4) by casein kinase 2 in prostate cancer cells. Cell Death and Disease, 5. https://doi.org/10.1038/cddis.2013.532

@article{953b28f320ec4de7b058c2f2f3f2442c,

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

abstract = "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.",

author = "{de Thonel}, A. and A. Hazoum{\'e} and V. Kochin and K. Isoniemi and G. Jego and E. Fourmaux and A. Hammann and H. Mjahed and O. Filhol and O. Micheau and P. Rocchi and V. Mezger and Eriksson, {J. E.} and Rangnekar, {V. M.} and C. Garrido",

note = "Funding Information: Acknowledgements. We thank Professor Sistonen (Turku Centre of Biotechnology, Finland), Dr. Downward (London Research institute, England), Dr. Robert (University of Manchester, England) for plasmid gifts, and Professor Schneider (University of Lausanne, Switzerland) for recombinant TRAIL. This work was supported by grants from the {\textquoteleft}Ligue Nationale Contre le Cancer{\textquoteright} and its committees in {\textquoteleft}Ni{\`e}vre{\textquoteleft}and {\textquoteleft}S{\^a}one et Loire{\textquoteright} and in part by funding from the NCI/NIH (grant CA60872 to VMR) AH is recipient of a post-doctoral fellowship from the {\textquoteleft}Conseil regional de Bourgogne{\textquoteright}, AdT has a post-doctoral fellowship from the {\textquoteleft}Association pour la Recherche contre le Cancer{\textquoteright}. CG{\textquoteright}s team has the {\textquoteleft}Label{\textquoteright} from the {\textquoteleft}Ligue Nationale contre le Cancer{\textquoteright}.",

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doi = "10.1038/cddis.2013.532",

language = "English",

volume = "5",

}

de Thonel, A, Hazoumé, A, Kochin, V, Isoniemi, K, Jego, G, Fourmaux, E, Hammann, A, Mjahed, H, Filhol, O, Micheau, O, Rocchi, P, Mezger, V, Eriksson, JE, Rangnekar, VM & Garrido, C 2014, 'Regulation of the proapoptotic functions of prostate apoptosis response-4 (Par-4) by casein kinase 2 in prostate cancer cells.', Cell Death and Disease, vol. 5. https://doi.org/10.1038/cddis.2013.532

TY - JOUR

T1 - Regulation of the proapoptotic functions of prostate apoptosis response-4 (Par-4) by casein kinase 2 in prostate cancer cells.

AU - de Thonel, A.

AU - Hazoumé, A.

AU - Kochin, V.

AU - Isoniemi, K.

AU - Jego, G.

AU - Fourmaux, E.

AU - Hammann, A.

AU - Mjahed, H.

AU - Filhol, O.

AU - Micheau, O.

AU - Rocchi, P.

AU - Mezger, V.

AU - Eriksson, J. E.

AU - Rangnekar, V. M.

AU - Garrido, C.

N1 - Funding Information: Acknowledgements. We thank Professor Sistonen (Turku Centre of Biotechnology, Finland), Dr. Downward (London Research institute, England), Dr. Robert (University of Manchester, England) for plasmid gifts, and Professor Schneider (University of Lausanne, Switzerland) for recombinant TRAIL. This work was supported by grants from the ‘Ligue Nationale Contre le Cancer’ and its committees in ‘Nièvre‘and ‘Sâone et Loire’ and in part by funding from the NCI/NIH (grant CA60872 to VMR) AH is recipient of a post-doctoral fellowship from the ‘Conseil regional de Bourgogne’, AdT has a post-doctoral fellowship from the ‘Association pour la Recherche contre le Cancer’. CG’s team has the ‘Label’ from the ‘Ligue Nationale contre le Cancer’.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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DO - 10.1038/cddis.2013.532

M3 - Article

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AN - SCOPUS:84906902902

VL - 5

JO - Cell Death and Disease

JF - Cell Death and Disease

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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