PhD thesis: a PhD thesis.
Protein kinase CK2 as a novel target for pro-senescence therapy in Pten null tumors
Université de Lausanne, Faculté de biologie et médecine
Faculté de biologie et de médecineUniversité de LausanneCH-1015 LausanneSUISSE
Prostate cancer, is one of the most common cancers in men worldwide (after lung cancer), and involves alterations of multiple tumor suppressor genes. In primary prostate cancers up to 70% of the patients have one allele of Pten loss and retain the other copy. Homozygous inactivation of PTEN is generally associated with advanced cancer and metastasis, supporting a possible key role for PTEN functional loss in tumor progression. Heterozygous loss of Pten is more tumorigenic than its complete loss. In the case of complete loss of Pten, it activates a p53-dependent cellular senescence, which acts as a fail-safe mechanism that opposes tumor progression. Cellular senescence is a stable cell cycle arrest that occurs in diploid cells during aging. However, diploid cells can also experience an accelerated senescence response, termed pre-mature senescence, driven by DNA-damage, oncogene over-expression or loss of tumour suppressor genes. Recent evidences demonstrate that cellular senescence occurs also in tumours, where it opposes tumour initiation and progression that can be exploited for cancer therapy. Currently, there are only a limited number of targeted therapies that act by increasing senescence in cancers, and the majority of them are not selective. Several novel strategies have been developed to promote senescence in tumours. This approach has been named pro-senescence therapy for cancer. Among the most promising pro-senescence therapies for cancer; there are compounds that can enhance or reactivate p53 in tumours, others block the cell cycle machinery and some inhibit telomerase. These compounds are currently in both pre-clinical and clinical trials. In addition, Senescence secretome reprogramming or induction of PTEN-induced cellular senescence have been recently proposed as promising therapeutic approach for the treatment of certain type of tumours. 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 II (CK2) as a pro-senescent target. Mechanistically, we show that Pten Joss increases CK2 levels by activating STAT3. CK2 up-regulation in Pten nul! turnors affects the stability of Pml, an essential regulator of senescence. However, CK2 inhibition stabilizes Pml levels enhancing senescence in Pten null tumors. Taken together, our screening strategy has identified a novel STAT3-CK2-PML network that can be targeted for pro senescence therapy for cancer. In conclusion, sti'ategies aimed to identify novel pro-senescence compounds would aid the development of more efficient treatment modalities for cancer therapy.
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