A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours

Madhuri Kalathur, Alberto Toso, Jingjing Chen, Ajinkya Revandkar, Claudia Danzer-Baltzer, Ilaria Guccini, Abdullah Alajati, Manuela Sarti, Sandra Pinton, Lara Brambilla, Diletta Di Mitri, Giuseppina Carbone, R Garcia-Escudero, Alessandro Padova, Letizia Magnoni, Alessia Tarditi, Laura Maccari, Federico Malusa, Ravi Kiran Reddy Kalathur, Lorenzo A. Pinna, Giorgio Cozza, Maria Ruzzene, Nicolas Delaleu, Carlo V. Catapano, Ian J. Frew and Andrea Alimonti ()
Additional contact information
Madhuri Kalathur: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Alberto Toso: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Jingjing Chen: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Ajinkya Revandkar: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Claudia Danzer-Baltzer: Institute of Physiology, University of Zurich
Ilaria Guccini: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Abdullah Alajati: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Manuela Sarti: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Sandra Pinton: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Lara Brambilla: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Diletta Di Mitri: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Giuseppina Carbone: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
R Garcia-Escudero: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Alessandro Padova: IRBM Science Park S.p.A.
Letizia Magnoni: Siena Biotech Spa
Alessia Tarditi: Siena Biotech Spa
Laura Maccari: Siena Biotech Spa
Federico Malusa: Siena Biotech Spa
Ravi Kiran Reddy Kalathur: Experimental & Clinical Cell Therapy Institute, Spinal Cord & Tissue Regeneration Center Salzburg, Paracelsus Medizinische Privatuniversität
Lorenzo A. Pinna: University of Padova, and VIMM
Giorgio Cozza: University of Padova, and VIMM
Maria Ruzzene: University of Padova, and VIMM
Nicolas Delaleu: Broegelmann Research Laboratory, University of Bergen
Carlo V. Catapano: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Ian J. Frew: Institute of Physiology, University of Zurich
Andrea Alimonti: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract Enhancement of cellular senescence in tumours triggers a stable cell growth arrest and activation of an antitumour immune response that can be exploited for cancer therapy. Currently, there are only a limited number of targeted therapies that act by increasing senescence in cancers, but the majority of them are not selective and also target healthy cells. Here we developed a chemogenomic screening to identify compounds that enhance senescence in PTEN-deficient cells without affecting normal cells. By using this approach, we identified casein kinase 2 (CK2) as a pro-senescent target. Mechanistically, we show that Pten loss increases CK2 levels by activating STAT3. CK2 upregulation in Pten null tumours affects the stability of Pml, an essential regulator of senescence. However, CK2 inhibition stabilizes Pml levels enhancing senescence in Pten null tumours. Taken together, our screening strategy has identified a novel STAT3–CK2–PML network that can be targeted for pro-senescence therapy for cancer.

Date: 2015
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DOI: 10.1038/ncomms8227

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