Oncotarget

Research Papers:

Integrated transcriptomic and proteomic analysis identifies protein kinase CK2 as a key signaling node in an inflammatory cytokine network in ovarian cancer cells

Hagen Kulbe, Francesco Iorio, Probir Chakravarty, Carla S. Milagre, Robert Moore, Richard G. Thompson, Gemma Everitt, Monica Canosa, Alexander Montoya, Denis Drygin, Ioana Braicu, Jalid Sehouli, Julio Saez-Rodriguez, Pedro R. Cutillas and Frances R. Balkwill _

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Oncotarget. 2016; 7:15648-15661. https://doi.org/10.18632/oncotarget.7255

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Abstract

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

Correspondence to:

Frances R. Balkwill, e-mail: [email protected]

Keywords: inflammatory cytokine networks, ovarian cancer, microenvironment, systems biology, therapeutics

Received: December 14, 2015     Accepted: January 26, 2016     Published: February 8, 2016

ABSTRACT

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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