Cancer Cell Signaling
Jukka Westermarck, Research Professor of the Finnish Cancer Institute
Turku Centre for Biotechnology
jukka.westermarck [at] utu.fi
Turku Centre for Biotechnology
P.O. Box 123, BioCity
(Street addr. Tykistökatu 6 B)
FIN-20521 Turku, Finland
+358-294502880 (Jukka Westermarck)
+358-294503790 (Group members)
Description of the project
Most characteristics of malignant cell growth are driven by phosphorylation dependent signaling pathways that are deregulated in cancer cells. Whereas the regulation and function of many oncogenic kinases are well understood, the role of protein phosphatases in determining the phosphorylation state and activity of phosphoproteins critical for cancer initiation and progression is yet poorly understood. Protein phosphatase 2A (PP2A) is a trimeric protein phosphatase complex consisting of catalytic C-subunit (PP2Ac), scaffolding A-subunit (PR65) and various regulatory B-subunits. Importantly, it has been estimated that collectively PP2A complexes can dephosphorylate vast majority of all cellular serine/threonine phosphorylated proteins. Importantly, inhibition of PP2A activity is a prerequisite for human cell transformation and thereby, by default, PP2A is inhibited in all human cancer cells. Regarding wide-spectrum role of PP2A on cellular signaling, it has been reasoned that re-activation of inhibited PP2A complexes would result in simultaneous inhibition of multiple oncogenic pathways. Our laboratory recently identified CIP2A as a novel PP2A inhibitor protein (Cell, 2007), and was first to demonstrate cancer-promoting roles for both CIP2A and another PP2A inhibitor protein PME-1 (Cancer Research, 2009). Expression of both of these proteins shows strong association with tumor progression in human patients (Cell, 2007, JNCI, 2009, Cancer Res. 2009, Cancer Discovery 2013).
The focus of our laboratory is to understand role and regulation of PP2A in human cancers and especially function of PP2A inhibitor proteins as human oncoproteins. To achieve this, we use a combination of advanced cell and molecular biology approaches combined with genetically modified mouse cancer models. We also have special interest on developing RNAi-based cancer therapies against PP2A inhibitor proteins. Our recent results suggest that a potential biological outcome of aberrant PP2A signaling in cancer is conferring drug resistance. Based both on these results, and on wide-spectrum role of PP2A on cellular signaling, we hypothesize that re-activation of PP2A, via targeting of its endogenous inhibitory proteins, could be used as a general strategy for multi-target inhibition of chemoresistance in common human cancer types. In addition, these results may have importance in patient stratification for monotherapies using the identified small molecule compounds.
Eleonora Mäkelä (née Sittig)
The Academy of Finland, University of Turku Graduate School/Turku Graduate School of Biomedical Sciences, Sigrid Juselius Foundation, Cancer Research Foundation of Finland, Jane and Aatos Erkko Foundation.