Regulation of the proapoptotic functions of prostate apoptosis response-4 (Par-4) by casein kinase 2 in prostate cancer cells.
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.
1] INSERM U866, Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France [2] Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France.
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de Thonel
1] INSERM U866, Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France [2] Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France.
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Hazoumé
Department of Pathology, Sapporo Medical University, Sapporo-shi, Hokkaido, Japan.
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Kochin
1] Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland [2] Department of Biosciences, Åbo Akademi University, Tykistökatu 6B, Turku, Finland.
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Isoniemi
1] INSERM U866, Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France [2] Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France.
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Jego
1] INSERM U866, Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France [2] Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France.
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Fourmaux
1] INSERM U866, Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France [2] Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France.
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Hammann
1] INSERM U866, Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France [2] Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France.
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Mjahed
INSERM U1036, DSV/iRTSV/CEA, Grenoble, France.
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Filhol
1] INSERM U866, Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France [2] Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France.
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Micheau
1] INSERM, U624 'Stress Cellulaire', Marseille, France [2] Aix-Marseille Université, Campus de Luminy, Marseille, France.
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Rocchi
1] CNRS, UMR7216 Épigénétique et Destin Cellulaire, 35 rue Hélène Brion, Paris, France [2] University Paris Diderot, Sorbonne Paris Cité, 35 rue Hélène Brion, Paris, France.
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Mezger
1] Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland [2] Department of Biosciences, Åbo Akademi University, Tykistökatu 6B, Turku, Finland.
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Eriksson
1] Department of Radiation Medicine, Lexington, KY, USA [2] Department of Microbiology, Immunology and Molecular Genetics, Lexington, KY, USA [3] Graduate Center for Toxicology, Lexington, KY, USA [4] Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
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Rangnekar
1] INSERM U866, Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France [2] Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France [3] Anticancer Center Jean François Leclerc, Dijon, France.
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Garrido
D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats
D051017:Apoptosis Regulatory Proteins; C101296:prostate apoptosis response-4 protein; D047390:Casein Kinase II