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


Kalathur, Madhuri; Toso, Alberto; Chen, Jingjing; et al (2015). A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours. Nature Communications, 6:7227.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2015
Deposited On:29 Feb 2016 16:01
Last Modified:17 Aug 2016 06:46
Publisher:Nature Publishing Group
ISSN:2041-1723
Funders:Swiss National Science Foundation (SNF) grant Ambizione (PZ00P3_136612/1), European Society for Medical Oncology (ESMO) translational research award, Swiss Bridge Award and European research council starting grant to A.A. (ERCsg 261342), ERCsg 260316, AIRC grant IG-14180
Publisher DOI:https://doi.org/10.1038/ncomms8227
PubMed ID:26085373

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