Protein kinase CK2 and cancer: addiction and therapeutic opportunities

Dr. Claude COCHET

INSERM 1036, Biologie du Cancer et de l’Infection iRTSV/BCI
CEA, Grenoble

11:00 VENDREDI 11 AVRIL, 2014

ENS LYON – Site Monod, 46, allée d’Italie, 69007 Lyon  – Salle des Thèses


Protein-kinase CK2 is a highly ubiquitous and multifaceted serine/threonine kinase described as a multisubunit holoenzyme generated by the tight association of two α or α’ catalytic subunits with a dimer of β regulatory subunits. Traditionally, CK2 has been regarded as a constitutively active protein-kinase in search of specific cellular functions. However, several studies have indicated that CK2 is a stress-activated kinase that plays a crucial role in the regulation of cell proliferation and in the transduction of survival signals. Aberrant activation of protein kinases is a key oncogenic force underlying human tumorigenesis and CK2 activity is unvariably elevated in cancer cells. Specifically, we showed that overexpression of CK2α in human breast a cancer is correlated with metastatic risk. In addition, in primary breast tumours, CK2β underexpression correlates strongly with expression of EMT markers, a process which is closely linked to conversion of early-stage tumours into invasive malignancies, emphasizing the link between asymmetric expression of CK2 subunits and EMT in vivo. In vitro, CK2β-depleted epithelial cells displayed EMT-like morphological changes, enhanced migration, anchorage-independent growth and stem cell-like properties, all of which require Snail1 induction. This process depends strongly on CK2β, thus confirming that CK2 functions upstream of Snail1. These results therefore highlight the importance of CK2β in controlling epithelial cell plasticity and suggest that unbalanced expression of CK2 subunits may drive EMT, thereby contributing to tumour progression. Consequently, CK2 has emerged as a relevant therapeutic target. We have identified several ATP competitive inhibitors targeting its active site, some of them exhibiting anti-tumoral activity. The molecular architecture of CK2 could offer opportunities to develop alternative strategies to inhibit CK2 functions. Using structure-based virtual screening approaches, we have identified several classes of small molecular mass inhibitors targeting different surface area on CK2α or at the CK2α/CK2β interface.

Selected references

Deshiere A, Duchemin-Pelletier E, Spreux E, Ciais D, Combes F, Vandenbrouck Y, Couté Y, Mikaelian I, Giusiano S, Charpin C, Cochet C, Filhol O. Unbalanced expression of CK2 kinase subunits is sufficient to drive epithelial-to-mesenchymal transition by Snail1 induction. Oncogene. (2013) 14;32(11):1373-83.

Moucadel V, Prudent R, Sautel CF, Teillet F, Barette C, Lafanechere L, Receveur-Brechot V, Cochet C. Antitumoral activity of allosteric inhibitors of protein kinase CK2. Oncotarget. (2011) 2(12):997-1010.

Prudent R, Moucadel V, Nguyen CH, Barette C, Schmidt F, Florent JC, Lafanechère L, Sautel CF, Duchemin-Pelletier E, Spreux E, Filhol O, Reiser JB Cochet C. Antitumor activity of pyridocarbazole and benzopyridoindole derivatives that inhibit protein kinase CK2. Cancer Res. (2010);70(23):9865- 74.

Host : Jérôme Kucharczak (