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  • Deux Séminaires à Lyon: « Protein kinase CH2 and cancer » et « Intercellular communication of cell fitness »

 

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 (jerome.kucharczak@ens-lyon.fr) 

 

 

 

 

Intercellular communication of Cell Fitness

Prof. Dr. Eduardo Moreno

Institute of Cell Biology (ICB) University of Bern, Switzerland

 

14:00 VENDREDI 18 AVRIL, 2014

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

 

Humans are able to detect fitness decay in other colleagues by simply looking at the graying of the hair or the wrinkles in their faces. Work from my laboratory in the last few years showed that cells can also detect fitness levels of neighboring cells using a molecular code. This molecular code is encoded by different isoforms of a transmembrane protein called Flower that creates a novel mechanism used to reveal the fitness of a cell to its neighbors. Those « fitness fingerprints » can be used to mediate cell selection by recognizing and eliminating less fit cells. In terms of basic biology, we are currently interested in the molecular and genetic mechanisms that drive active cell selection within tissues. In terms of more applied science, we want to explore how disruption of the mechanisms that mediate cell selection create tissue degeneration, including neurodegeneration, cancer and aging.

Selected references

  1. Merino MM, Rhiner C, Portela M, Moreno E. (2013). « Fitness fingerprints » mediate physiological culling of unwanted neurons in Drosophila. Curr Biol. 23:1300-9. doi: 10.1016/j.cub.2013.05.053. Epub 2013 Jun 27.

  2. Lolo, F., Casas-Tinto S. and Moreno E. (2012). Cell competition timeline: winners kill losers, which are extruded and engulfed by hemocytes. Cell reports 2:526-539. DOI: 10.1016/j.celrep.2012.08.012.

  3. Rhiner C, López-Gay JM, Soldini D, Casas-Tinto S, Martín FA, Lombardía L, Moreno E. (2010). Flower Forms an Extracellular Code that Reveals the Fitness of a Cell to its Neighbors in Drosophila. Dev. Cell 18:985-998.

Hosts : Bertrand Mollereau and François Leulier (bertrand.mollereau@ens-lyon.fr and francois.leulier@ens-lyon.fr)