Integrated transcriptomic and proteomic analysis identifies protein kinase CK2 as a key signaling node in an inflammatory cytokine network in ovarian cancer cells
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Hagen Kulbe1,8, Francesco Iorio4,6, Probir Chakravarty3, Carla S. Milagre1, Robert Moore1, Richard G. Thompson1, Gemma Everitt1, Monica Canosa1, Alexander Montoya2, Denis Drygin5, Ioana Braicu7,8, Jalid Sehouli7,8, Julio Saez-Rodriguez4, Pedro R. Cutillas2, Frances R. Balkwill1
1Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London, UK
2Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
3Bioinformatics Core, The Francis Crick Institute, London, UK
4European Molecular Biology Laboratory – European Bioinformatics Institute, EMBL-EBI, Cambridge, UK
5Pimera, Inc., San Diego, CA, USA
6Cancer Genome Project, Wellcome Trust Sanger Institute, Cambridge, UK
7Tumorbank Ovarian Cancer Network, Department of Gynecology, Charité Universitätsmedizin Berlin, Berlin, Germany
8Department of Gynecology, Charité Universitätsmedizin Berlin, Berlin, Germany
Frances R. Balkwill, e-mail: email@example.com
Keywords: inflammatory cytokine networks, ovarian cancer, microenvironment, systems biology, therapeutics
Received: December 14, 2015 Accepted: January 26, 2016 Published: February 8, 2016
We previously showed how key pathways in cancer-related inflammation and Notch signaling are part of an autocrine malignant cell network in ovarian cancer. This network, which we named the “TNF network”, has paracrine actions within the tumor microenvironment, influencing angiogenesis and the immune cell infiltrate.
The aim of this study was to identify critical regulators in the signaling pathways of the TNF network in ovarian cancer cells that might be therapeutic targets. To achieve our aim, we used a systems biology approach, combining data from phospho-proteomic mass spectrometry and gene expression array analysis. Among the potential therapeutic kinase targets identified was the protein kinase Casein kinase II (CK2).
Knockdown of CK2 expression in malignant cells by siRNA or treatment with the specific CK2 inhibitor CX-4945 significantly decreased Notch signaling and reduced constitutive cytokine release in ovarian cancer cell lines that expressed the TNF network as well as malignant cells isolated from high grade serous ovarian cancer ascites. The expression of the same cytokines was also inhibited after treatment with CX-4945 in a 3D organotypic model. CK2 inhibition was associated with concomitant inhibition of proliferative activity, reduced angiogenesis and experimental peritoneal ovarian tumor growth.
In conclusion, we have identified kinases, particularly CK2, associated with the TNF network that may play a central role in sustaining the cytokine network and/or mediating its effects in ovarian cancer.
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