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Inhibition of protein kinase CK2 expression and activity blocks tumor cell growth

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Abstract

Protein kinase CK2 (CK2) is a highly conserved and ubiquitous serine/threonine kinase. It is a multifunctional and pleiotropic protein kinase implicated in the regulation of cell proliferation, survival, and differentiation. Deregulation of CK2 is observed in a wide variety of tumors. It has been the focus of intensive research efforts to establish the cause–effect relationship between CK2 and neoplastic growth. Here, we further validate the role of CK2 in cancer cell growth using siRNA approach. We also screened a library of more than 200,000 compounds and identified several molecules, which inhibit CK2 with IC50 < 1 μM. The binding mode of a representative compound with maize CK2 was determined. In addition, the cellular activity of the compounds was demonstrated by their inhibition of phosphorylation of PTEN Ser370 in HCT116 cells. Treatment of a variety of cancer cell lines with the newly identified CK2 inhibitor significantly blocked cell growth with IC50s as low as 300 nM.

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Abbreviations

CK2:

Protein kinase CK2

siRNA:

Small interfering RNA

TBB:

4,5,6,7-Tetrabromobenzotriazole

DRB:

5,6-Dichloro-β-ribofuranosylbenzimidazole

HTS:

High throughput screening

HTRF:

Homogenous time resolved fluorescence

FRET:

Fluorescence resonance energy transfer

HDAC:

Histone deacetylase

ATP:

Adenosine-5′-triphosphate

EDTA:

Ethylenediaminetetraacetic acid

Eu:

Europium

μCi:

Micro Curie

Ki:

Dissociation constant

Km:

Substrate concentration that results in half-maximal velocity for the enzymatic reaction

zmCK2α:

Maize protein kinase CK2α

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Author notes

  1. Owen Pornillos

    Present address: Department of Molecular Physiology & Biological Physics, University of Virginia, Charlottesville, VA, 22908, USA

  2. Xuequn Helen Hua

    Present address: Ambit Biosciences, 4215 Sorrento Valley Boulevard, San Diego, CA, 92121, USA

  3. Sarah Cox

    Present address: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA, 92121, USA

Authors and Affiliations

  1. Celgene Corporation, 4550 Towne Centre Court, San Diego, CA, 92121, USA

    Dan Zhu, Jennifer Hensel, Robert Hilgraf, Mahan Abbasian, Owen Pornillos, Gordafaried Deyanat-Yazdi, Xuequn Helen Hua & Sarah Cox

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  1. Dan Zhu
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Correspondence to Dan Zhu.

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Zhu, D., Hensel, J., Hilgraf, R. et al. Inhibition of protein kinase CK2 expression and activity blocks tumor cell growth. Mol Cell Biochem 333, 159–167 (2010). https://doi.org/10.1007/s11010-009-0216-0

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