Journal of Molecular Medicine

, Volume 98, Issue 1, pp 123–133 | Cite as

Protein kinase CK2 contributes to placental development: physiological and pathological implications

  • Roland Abi NahedEmail author
  • Deborah Reynaud
  • Nicolas Lemaitre
  • Solene Lartigue
  • Caroline Roelants
  • Daniel Vaiman
  • Mohamed Benharouga
  • Claude Cochet
  • Odile Filhol
  • Nadia Alfaidy
Original Article


Preeclampsia (PE) is the most threatening pathology of human pregnancy. Its development is thought to be due to a failure in the invasion of trophoblast cells that establish the feto-maternal circulation. Protein kinase CK2 is a ubiquitous enzyme reported to be involved in the control of cell invasion. CK2 consists of two subunits, a catalytic subunit, CK2α, and a regulatory subunit, CK2β. To date, no data exist regarding the expression and role of this enzyme in normal and PE pregnancies. We performed studies, at the clinical level using distinctive cohorts from early pregnancy (n = 24) and from PE (n = 23) and age-matched controls (n = 28); in vitro, using trophoblast cell lines; ex vivo, using placental explants; and in vivo, using PE mouse models. We demonstrated that (i) CK2 is more expressed during the late first trimester of pregnancy and is mainly localized in differentiated trophoblast cells, (ii) the inhibition of its enzymatic activity decreased the proliferation, migration, invasion, and syncytialization of trophoblast cells, both in 2D and 3D culture systems, and (iii) CK2 activity and the CK2α/CK2β protein ratio were increased in PE human placentas. The pattern and profile of CK2 expression were confirmed in gravid mice along with an increase in the PE mouse models. Altogether, our results demonstrate that CK2 plays an essential role in the establishment of the feto-maternal circulation and that its deregulation is associated with PE development. The increase in CK2 activity in PE might constitute a compensatory mechanism to ensure proper pregnancy progress.


Placenta Protein kinase CK2 Preeclampsia Animal model Trophoblast invasion 



We also thank Ms. Sophie Ndagijimana and Ms. Aude Salomon for their technical assistance.

Funding information

We acknowledge the following sources of fundings: Institut National de la Santé et de la Recherche Médicale (U1036), University Grenoble-Alpes, Commissariat à l’Energie Atomique (DRF/IRIG/BCI), Région Auvergne-Rhône-Alpes “CLARA”, Ligue Nationale contre le Cancer and Ligue Départementale (Isère) and Fondation pour la recherche Médicale (FRM) SPF20150934074.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

109_2019_1855_MOESM1_ESM.docx (35 kb)
ESM 1 (DOCX 35 kb)


  1. 1.
    Sibai B, Dekker G, Kupferminc M (2005) Pre-eclampsia. Lancet 365:785–799CrossRefGoogle Scholar
  2. 2.
    Roberts JM, Redman CW (1993) Pre-eclampsia: more than pregnancy-induced hypertension. Lancet 341:1447–1451CrossRefGoogle Scholar
  3. 3.
    Burton GJ (2009) Oxygen, the Janus gas; its effects on human placental development and function. J Anat 215:27–35CrossRefGoogle Scholar
  4. 4.
    Jauniaux E, Watson AL, Hempstock J, Bao YP, Skepper JN, Burton GJ (2000) Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure. Am J Pathol 157:2111–2122CrossRefGoogle Scholar
  5. 5.
    Huppertz B, Gauster M, Orendi K, Konig J, Moser G (2009) Oxygen as modulator of trophoblast invasion. J Anat 215:14–20CrossRefGoogle Scholar
  6. 6.
    Mistry HD, Williams PJ (2011) The importance of antioxidant micronutrients in pregnancy. Oxidative Med Cell Longev 2011:841749CrossRefGoogle Scholar
  7. 7.
    Tortladze M, Kintraia N, Parkauli M, Sanikidze T (2013) [Blood antioxidant enzyme activity during physiological and preeclampsia syndrome complicated pregnancy]. Georgian Med News 215:12–16Google Scholar
  8. 8.
    Watson AL, Palmer ME, Jauniaux E, Burton GJ (1997) Variations in expression of copper/zinc superoxide dismutase in villous trophoblast of the human placenta with gestational age. Placenta 18:295–299CrossRefGoogle Scholar
  9. 9.
    Pfeiffer A, Jaeckel M, Lewerenz J, Noack R, Pouya A, Schacht T, Hoffmann C, Winter J, Schweiger S, Schafer MK et al (2014) Mitochondrial function and energy metabolism in neuronal HT22 cells resistant to oxidative stress. Br J Pharmacol 171:2147–2158CrossRefGoogle Scholar
  10. 10.
    Wilkinson ST, Tome ME, Briehl MM (2012) Mitochondrial adaptations to oxidative stress confer resistance to apoptosis in lymphoma cells. Int J Mol Sci 13:10212–10228CrossRefGoogle Scholar
  11. 11.
    Kim GS, Jung JE, Narasimhan P, Sakata H, Yoshioka H, Song YS, Okami N, Chan PH (2012) Release of mitochondrial apoptogenic factors and cell death are mediated by CK2 and NADPH oxidase. J Cereb Blood Flow Metab 32:720–730CrossRefGoogle Scholar
  12. 12.
    Bibby AC, Litchfield DW (2005) The multiple personalities of the regulatory subunit of protein kinase CK2: CK2 dependent and CK2 independent roles reveal a secret identity for CK2beta. Int J Biol Sci 1:67–79CrossRefGoogle Scholar
  13. 13.
    Filhol O, Giacosa S, Wallez Y, Cochet C (2015) Protein kinase CK2 in breast cancer: the CK2beta regulatory subunit takes center stage in epithelial plasticity. Cell Mol Life Sci 72:3305–3322CrossRefGoogle Scholar
  14. 14.
    Buchou T, Vernet M, Blond O, Jensen HH, Pointu H, Olsen BB, Cochet C, Issinger OG, Boldyreff B (2003) Disruption of the regulatory beta subunit of protein kinase CK2 in mice leads to a cell-autonomous defect and early embryonic lethality. Mol Cell Biol 23:908–915CrossRefGoogle Scholar
  15. 15.
    Zanin S, Sandre M, Cozza G, Ottaviani D, Marin O, Pinna LA, Ruzzene M (2015) Chimeric peptides as modulators of CK2-dependent signaling: Mechanism of action and off-target effects. Biochim Biophys Acta 1854:1694–1707CrossRefGoogle Scholar
  16. 16.
    Pinna LA (2002) Protein kinase CK2: a challenge to canons. J Cell Sci 115:3873–3878CrossRefGoogle Scholar
  17. 17.
    Filhol O, Nueda A, Martel V, Gerber-Scokaert D, Benitez MJ, Souchier C, Saoudi Y, Cochet C (2003) Live-cell fluorescence imaging reveals the dynamics of protein kinase CK2 individual subunits. Mol Cell Biol 23:975–987CrossRefGoogle Scholar
  18. 18.
    Deshiere A, Duchemin-Pelletier E, Spreux E, Ciais D, Combes F, Vandenbrouck Y, Coute Y, Mikaelian I, Giusiano S, Charpin C et al (2013) Unbalanced expression of CK2 kinase subunits is sufficient to drive epithelial-to-mesenchymal transition by Snail1 induction. Oncogene 32:1373–1383CrossRefGoogle Scholar
  19. 19.
    Ahmed K, Gerber DA, Cochet C (2002) Joining the cell survival squad: an emerging role for protein kinase CK2. Trends Cell Biol 12:226–230CrossRefGoogle Scholar
  20. 20.
    Montenarh M (2014) Protein kinase CK2 and angiogenesis. Adv Clin Experiment Med: Off Organ Wroclaw Med Univ 23:153–158CrossRefGoogle Scholar
  21. 21.
    Watabe M, Nakaki T (2012) CK2 as anti-stress factor. Commun Integr Biol 5:278–280CrossRefGoogle Scholar
  22. 22.
    Alfaidy N, Gupta S, DeMarco C, Caniggia I, Challis JR (2002) Oxygen regulation of placental 11 beta-hydroxysteroid dehydrogenase 2: physiological and pathological implications. J Clin Endocrinol Metab 87:4797–4805CrossRefGoogle Scholar
  23. 23.
    Siddiqui-Jain A, Drygin D, Streiner N, Chua P, Pierre F, O'Brien SE, Bliesath J, Omori M, Huser N, Ho C, Proffitt C, Schwaebe MK, Ryckman DM, Rice WG, Anderes K (2010) CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res 70:10288–10298CrossRefGoogle Scholar
  24. 24.
    Salizzato V, Zanin S, Borgo C, Lidron E, Salvi M, Rizzuto R, Pallafacchina G, Donella-Deana A (2019) Protein kinase CK2 subunits exert specific and coordinated functions in skeletal muscle differentiation and fusogenic activity. FASEB J 33:10648–10667CrossRefGoogle Scholar
  25. 25.
    Doridot L, Passet B, Mehats C, Rigourd V, Barbaux S, Ducat A, Mondon F, Vilotte M, Castille J, Breuiller-Fouche M et al (2013) Preeclampsia-like symptoms induced in mice by fetoplacental expression of STOX1 are reversed by aspirin treatment. Hypertension 61:662–668CrossRefGoogle Scholar
  26. 26.
    Sergent F, Hoffmann P, Brouillet S, Garnier V, Salomon A, Murthi P, Benharouga M, Feige JJ, Alfaidy N (2016) Sustained endocrine gland-derived vascular endothelial growth factor levels beyond the first trimester of pregnancy display phenotypic and functional changes associated with the pathogenesis of pregnancy-induced hypertension. Hypertension 68:148–156CrossRefGoogle Scholar
  27. 27.
    Chesley LC (1985) Diagnosis of preeclampsia. Obstet Gynecol 65:423–425PubMedGoogle Scholar
  28. 28.
    Chelbi ST, Vaiman D (2008) Genetic and epigenetic factors contribute to the onset of preeclampsia. Mol Cell Endocrinol 282:120–129CrossRefGoogle Scholar
  29. 29.
    Hoffmann P, Saoudi Y, Benharouga M, Graham CH, Schaal JP, Mazouni C, Feige JJ, Alfaidy N (2009) Role of EG-VEGF in human placentation: physiological and pathological implications. J Cell Mol Med 13:2224–2235CrossRefGoogle Scholar
  30. 30.
    van Dijk M, Mulders J, Poutsma A, Konst AA, Lachmeijer AM, Dekker GA, Blankenstein MA, Oudejans CB (2005) Maternal segregation of the Dutch preeclampsia locus at 10q22 with a new member of the winged helix gene family. Nat Genet 37:514–519CrossRefGoogle Scholar
  31. 31.
    Rigourd V, Chauvet C, Chelbi ST, Rebourcet R, Mondon F, Letourneur F, Mignot TM, Barbaux S, Vaiman D (2008) STOX1 overexpression in choriocarcinoma cells mimics transcriptional alterations observed in preeclamptic placentas. PLoS One 3:e3905. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Garnier V, Traboulsi W, Salomon A, Brouillet S, Fournier T, Winkler C, Desvergne B, Hoffmann P, Zhou QY, Congiu C, Onnis V, Benharouga M, Feige JJ, Alfaidy N (2015) PPARgamma controls pregnancy outcome through activation of EG-VEGF: new insights into the mechanism of placental development. Am J Phys Endocrinol Metab 309:E357–E369CrossRefGoogle Scholar
  33. 33.
    Filhol O, Ciais D, Lajaunie C, Charbonnier P, Foveau N, Vert JP, Vandenbrouck Y (2012) DSIR: assessing the design of highly potent siRNA by testing a set of cancer-relevant target genes. PLoS One 7:e48057. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Alfaidy N, Chauvet S, Donadio-Andrei S, Salomon A, Saoudi Y, Richaud P, Aude-Garcia C, Hoffmann P, Andrieux A, Moulis JM, Feige JJ, Benharouga M (2013) Prion protein expression and functional importance in developmental angiogenesis: role in oxidative stress and copper homeostasis. Antioxid Redox Signal 18:400–411CrossRefGoogle Scholar
  35. 35.
    Hung TH, Burton GJ (2006) Hypoxia and reoxygenation: a possible mechanism for placental oxidative stress in preeclampsia. Taiwan J Obstet Gynecol 45:189–200CrossRefGoogle Scholar
  36. 36.
    Schoots MH, Gordijn SJ, Scherjon SA, van Goor H, Hillebrands JL (2018) Oxidative stress in placental pathology. Placenta 69:153–161CrossRefGoogle Scholar
  37. 37.
    Good AG, Paetkau DH (1992) Identification and characterization of a hypoxically induced maize lactate dehydrogenase gene. Plant Mol Biol 19:693–697CrossRefGoogle Scholar
  38. 38.
    Webster KA, Gunning P, Hardeman E, Wallace DC, Kedes L (1990) Coordinate reciprocal trends in glycolytic and mitochondrial transcript accumulations during the in vitro differentiation of human myoblasts. J Cell Physiol 142:566–573CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Roland Abi Nahed
    • 1
    • 2
    • 3
    Email author
  • Deborah Reynaud
    • 1
    • 2
    • 3
  • Nicolas Lemaitre
    • 1
    • 2
    • 3
  • Solene Lartigue
    • 1
    • 2
    • 3
  • Caroline Roelants
    • 1
    • 2
    • 3
    • 4
  • Daniel Vaiman
    • 5
  • Mohamed Benharouga
    • 2
    • 3
    • 6
  • Claude Cochet
    • 1
    • 2
    • 3
  • Odile Filhol
    • 1
    • 2
    • 3
  • Nadia Alfaidy
    • 1
    • 2
    • 3
  1. 1.Institut National de la Santé et de la Recherche MédicaleGrenobleFrance
  2. 2.Université Grenoble-AlpesGrenobleFrance
  3. 3.Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA)Interdisciplinary Research Institure of Grenoble (IRIG)GrenobleFrance
  4. 4.InovarionParisFrance
  5. 5.Genomics, Epigenetics and Physiopathology of ReproductionInstitut Cochin, U1016 Inserm- UMR 8104 CNRS - Paris-Descartes UniversityParisFrance
  6. 6.Laboratoire de Chimie et Biologie des MétauxCentre National de la Recherche Scientifique, Unité Mixte de Recherche 5249GrenobleFrance

Personalised recommendations