Resumen
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.
| Idioma original | English |
|---|---|
| Publicación | Cell Death and Disease |
| Volumen | 5 |
| DOI | |
| Estado | Published - 2014 |
Nota bibliográfica
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’.
Financiación
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’.
| Financiadores | Número del financiador |
|---|---|
| Conseil regional de Bourgogne | |
| NCI/NIH | |
| National Childhood Cancer Registry – National Cancer Institute | R01CA060872 |
| National Childhood Cancer Registry – National Cancer Institute | |
| Association pour la Recherche sur le Cancer | |
| Ligue Contre le Cancer |
ASJC Scopus subject areas
- Immunology
- Cellular and Molecular Neuroscience
- Cell Biology
- Cancer Research
ODS de las Naciones Unidas
Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible
