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.
Highlights
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
Using chemogenomic and short hairpin RNA approaches, we found that the inhibition of casein kinase 2 (CK2) enhances PTEN loss-induced cellular senescence (PICS) without affecting normal cells
Our study demonstrates that the upregulation of CK2 in Pten null tumours is mediated by activation of Stat[3], which is highly phosphorylated in Pten null tumours
Summary
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. Identification of novel genes that regulate senescence in PTEN-deficient tumours without affecting normal cells would help to develop more effective and selective pro-senescence compounds for the treatment of different types of cancer[3]. This may be relevant for prostate cancer therapy since PTEN-deficient prostate tumours conserve an intact p53 response even at late stage of tumorigenesis and may benefit from treatments that enhance senescence by targeting p53 or its regulators. Our results demonstrate that CK2 is selectively upregulated in PTEN null cells and tumours and opposes PICS by affecting the stability of the promyelocytic leukaemia protein, PML, a known regulator of senescence in cancer[5]. Our data provide new insight into the mechanisms that drive senescence evasion in tumour cells and validate the effectiveness of an integrated approach for the identification of ‘pro-senescence’ compounds in PTEN-deficient tumours
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