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

Details

Serval ID
serval:BIB_2D7836A9FF3B
Type
Article: article from journal or magazin.
Collection
Publications
Title
A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours.
Journal
Nature Communications
Author(s)
Kalathur M., Toso A., Chen J., Revandkar A., Danzer-Baltzer C., Guccini I., Alajati A., Sarti M., Pinton S., Brambilla L., Di Mitri D., Carbone G., Garcia-Escudero R., Padova A., Magnoni L., Tarditi A., Maccari L., Malusa F., Kalathur R.K., A Pinna L., Cozza G., Ruzzene M., Delaleu N., Catapano C.V., Frew I.J., Alimonti A.
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
6
Pages
7227
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
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.
Keywords
Animals, Casein Kinase II/antagonists & inhibitors, Casein Kinase II/metabolism, Cell Aging/drug effects, Drug Evaluation, Preclinical, Female, HCT116 Cells, Humans, Male, Mice, Transgenic, Molecular Targeted Therapy, Naphthyridines/pharmacology, Naphthyridines/therapeutic use, Nuclear Proteins/metabolism, PTEN Phosphohydrolase/deficiency, Prostatic Neoplasms/drug therapy, RNA, Small Interfering, STAT3 Transcription Factor/metabolism, Transcription Factors/metabolism, Tumor Suppressor Proteins/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
24/07/2015 17:14
Last modification date
20/08/2019 13:12
Usage data