title: A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours.
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.
authors.affiliation: 1] Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), CH 6500 Bellinzona, Switzerland [2] Faculty of Biology and Medicine, University of Lausanne (UNIL), CH-1011 Lausanne, Switzerland.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Kalathur
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), CH 6500 Bellinzona, Switzerland.
authors.forename: Alberto
authors.initials: A
authors.lastname: Toso
authors.affiliation: 1] Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), CH 6500 Bellinzona, Switzerland [2] Faculty of Biology and Medicine, University of Lausanne (UNIL), CH-1011 Lausanne, Switzerland.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Chen
authors.affiliation: 1] Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), CH 6500 Bellinzona, Switzerland [2] Faculty of Biology and Medicine, University of Lausanne (UNIL), CH-1011 Lausanne, Switzerland.
authors.forename: Ajinkya
authors.initials: A
authors.lastname: Revandkar
authors.affiliation: 1] Institute of Physiology, University of Zurich, CH8006 Zurich, Switzerland [2] Zurich Center for Integrative Human Physiology, University of Zurich, CH8006 Zurich, Switzerland [3] Competence Center for Systems Physiology and Metabolic Diseases, CH8006 ETH Zurich, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Danzer-Baltzer
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), CH 6500 Bellinzona, Switzerland.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Guccini
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), CH 6500 Bellinzona, Switzerland.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Alajati
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), CH 6500 Bellinzona, Switzerland.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sarti
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), CH 6500 Bellinzona, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pinton
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), CH 6500 Bellinzona, Switzerland.
authors.forename: Lara
authors.initials: L
authors.lastname: Brambilla
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), CH 6500 Bellinzona, Switzerland.
authors.forename: Diletta
authors.initials: D
authors.lastname: Di Mitri
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), CH 6500 Bellinzona, Switzerland.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Carbone
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), CH 6500 Bellinzona, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Garcia-Escudero
authors.affiliation: IRBM Science Park S.p.A., 00040 Pomezia (Roma), Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padova
authors.affiliation: Siena Biotech Spa, 53100 Siena, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Magnoni
authors.affiliation: Siena Biotech Spa, 53100 Siena, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Tarditi
authors.affiliation: Siena Biotech Spa, 53100 Siena, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Maccari
authors.affiliation: Siena Biotech Spa, 53100 Siena, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Malusa
authors.affiliation: Experimental &Clinical Cell Therapy Institute, Spinal Cord &Tissue Regeneration Center Salzburg, Paracelsus Medizinische Privatuniversität, Strubergasse 21, A-5020, Salzburg, Austria.
authors.forename: Ravi Kiran Reddy
authors.identifier: 0000000328943345
authors.initials: RK
authors.lastname: Kalathur
authors.affiliation: Department of Biomedical Sciences, University of Padova, and VIMM, 35131 Padua, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: A Pinna
authors.affiliation: Department of Biomedical Sciences, University of Padova, and VIMM, 35131 Padua, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cozza
authors.affiliation: Department of Biomedical Sciences, University of Padova, and VIMM, 35131 Padua, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Ruzzene
authors.affiliation: Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Delaleu
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), CH 6500 Bellinzona, Switzerland.
authors.forename: Carlo V
authors.initials: CV
authors.lastname: Catapano
authors.affiliation: 1] Institute of Physiology, University of Zurich, CH8006 Zurich, Switzerland [2] Zurich Center for Integrative Human Physiology, University of Zurich, CH8006 Zurich, Switzerland [3] Competence Center for Systems Physiology and Metabolic Diseases, CH8006 ETH Zurich, Switzerland.
authors.forename: Ian J
authors.identifier: 0000000327355509
authors.initials: IJ
authors.lastname: Frew
authors.affiliation: 1] Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), CH 6500 Bellinzona, Switzerland [2] Faculty of Biology and Medicine, University of Lausanne (UNIL), CH-1011 Lausanne, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Alimonti
mesh_terms: D000818:Animals; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009287:Naphthyridines / Q000494:pharmacology / Q000627:therapeutic use*; D009687:Nuclear Proteins / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D010619:Phenazines; D000071156:Promyelocytic Leukemia Protein; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D009287:Naphthyridines; D009687:Nuclear Proteins; D010619:Phenazines; D000071156:Promyelocytic Leukemia Protein; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C555142:silmitasertib; D047390:Casein Kinase II; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human