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

Kalathur, Madhuri; Toso, Alberto; Chen, Jing Jing; Revandkar, Ajinkya; Danzer-Baltzer, Claudia; Guccini, Ilaria; Alajati, Abdullah; Sarti, Manuela; Pinton, Sandra; Brambilla, Lara; Mitri, Diletta Di; Carbone, Giuseppina M.; García-Escudero, Ramón; Padova, Alessandro; Magnoni, Letizia; Tarditi, Alessia; Maccari, Laura; Malusa, Federico; Kalathur, Ravi Kiran Reddy; Pinna, Lorenzo A.; Cozza, Giorgio; Ruzzene, Maria; Delaleu, Nicolas; Catapano, Carlo V.; Frew, Ian J.; Alimonti, Andrea

doi:10.1038/ncomms8227

Cited by 40 publications

(37 citation statements)

References 52 publications

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“…Among these, PDK1 and CK2 showed increased activity in high cytokine producing IGROV-1 cells compared with its TNF network inhibited form (shCXCR4 cells). Since PDK1 and CK2 are involved in the regulation of the PI3K/AKT pathway, we have confirmed these findings by visualizing the phosphorylation of PDK1 and the CK2 specific phosphorylation of AKT (Ser129), a phosphorylation site that is often used as a marker of CK2 activity by Western blot analysis (Figure 1C ) [ 29 , 30 ]. Phosphorylation of PDK1 (Ser241), PI3K (Tyr458), AKT (Ser473 and Ser129), were reduced in the shCXCR4 cells in which the TNF network has been inhibited.…”

Section: Resultssupporting

confidence: 65%

Integrated transcriptomic and proteomic analysis identifies protein kinase CK2 as a key signaling node in an inflammatory cytokine network in ovarian cancer cells

et al. 2016

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We previously showed how key pathways in cancer-related inflammation and Notch signaling are part of an autocrine malignant cell network in ovarian cancer. This network, which we named the “TNF network”, has paracrine actions within the tumor microenvironment, influencing angiogenesis and the immune cell infiltrate.The aim of this study was to identify critical regulators in the signaling pathways of the TNF network in ovarian cancer cells that might be therapeutic targets. To achieve our aim, we used a systems biology approach, combining data from phospho-proteomic mass spectrometry and gene expression array analysis. Among the potential therapeutic kinase targets identified was the protein kinase Casein kinase II (CK2).Knockdown of CK2 expression in malignant cells by siRNA or treatment with the specific CK2 inhibitor CX-4945 significantly decreased Notch signaling and reduced constitutive cytokine release in ovarian cancer cell lines that expressed the TNF network as well as malignant cells isolated from high grade serous ovarian cancer ascites. The expression of the same cytokines was also inhibited after treatment with CX-4945 in a 3D organotypic model. CK2 inhibition was associated with concomitant inhibition of proliferative activity, reduced angiogenesis and experimental peritoneal ovarian tumor growth.In conclusion, we have identified kinases, particularly CK2, associated with the TNF network that may play a central role in sustaining the cytokine network and/or mediating its effects in ovarian cancer.

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Section: Resultssupporting

confidence: 65%

Integrated transcriptomic and proteomic analysis identifies protein kinase CK2 as a key signaling node in an inflammatory cytokine network in ovarian cancer cells

et al. 2016

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“…Given these premises, it is not surprising that quinalizarin is effective in many disease models in which CK2 is effectively implicated, thus confirming CK2 as the principal target of this molecule. Recently quinalizarin has provided a strong argument to support the concept that CK2 may represent an appealing target for prosenescence antitumor strategies [ 28 ]. From a molecular point of view a detailed crystallographic study of the binding mode between quinalizarin and CK2 α subunit has been performed; initially cocrystallyzed with Zea Mays CK2 at pH 7.5 (PDB code: 3FL5 [ 10 ]), later the complex between quinalizarin and human CK2 was solved at pH 6.5 and 8.5 (PDB codes: 3Q9Z and 3Q9Y, resp.…”

Section: Introductionmentioning

confidence: 99%

The Selectivity of CK2 Inhibitor Quinalizarin: A Reevaluation

Cozza

Venerando

Sarno

et al. 2015

BioMed Research International

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Many polyphenolic compounds have been reported to inhibit protein kinases, with special reference to CK2, a pleiotropic serine/threonine kinase, implicated in neoplasia, neurodegenerative disease, and viral infections. In general however these compounds are not endowed with stringent selectivity. Among them quinalizarin (1,2,5,8-tetrahydroxyanthraquinone) turned out to be particularly potent (Ki = 0.058 μM) and quite selective as judged by profiling it on a small panel of 70 protein kinases. Here, by profiling quinalizarin on a larger panel of 140 kinases we reach the conclusion that quinalizarin is one of the most selective inhibitors of CK2, superior to the first-in-class CK2 inhibitor, CX-4945, now in clinical trials for the treatment of cancer. Moreover here we show that quinalizarin is able to discriminate between the isolated CK2 catalytic subunit (CK2α) and CK2 holoenzyme (CK2α 2 β 2), consistent with in silico and in vitro analyses.

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“…ERK5/CKII is involved in GPIb-IX-mediated platelet activation via regulation of the PTEN/PI3K/Akt pathway CKII is composed of two a subunits and two b subunits, and it phosphorylates serine/threonine/tyrosine of its substrate [26,27]. It has been reported that CKII can phosphorylate and attenuate the activity of phosphatase and tensin homolog deleted on chromosome ten (PTEN) [28]. Whether ERK5/CKII was involved in GPIb-IX-mediated platelet activation through regulation of PTEN phosphorylation requires investigation.…”

Section: Ckii Is One Of Erk5-associated Proteinsmentioning

confidence: 99%

Extracellular signal‐regulated kinase 5 associates with casein kinase II to regulate GPIb‐IX‐mediated platelet activation via the PTEN/PI3K/Akt pathway

Cheng

Gao

Fan

et al. 2017

Journal of Thrombosis and Haemostasis

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Background The platelet glycoprotein (GP) Ib-IX complex plays essential roles in thrombosis and hemostasis. The mitogen-activated protein kinases (MAPKs) ERK1/2 and p38 have been shown to be important in the GPIb-IX-mediated signaling leading to integrin activation. However, the roles of the MAPK extracellular signal-regulated kinase 5 (ERK5) in GPIb-IX-mediated platelet activation are unknown. Objective To reveal the function and mechanisms of ERK5 in GPIb-IX-mediated platelet activation. Methods The functions of ERK5 in GPIb-IX-mediated human platelet activation were assessed using botrocetin/VWF, ristocetin/VWF, or platelet adhesion to von Willebrand factor (VWF) under shear stress in the presence of a specific inhibitor of ERK5. ERK5-associated proteins were pulled down from Chinese hamster ovary (CHO) cells transfected with HA-tagged-ERK5, identified by mass spectrometry, and confirmed in human platelets. Roles of ERK5-associated proteins in GPIb-IX-mediated platelet activation were clarified using specific inhibitors. Results The phosphorylation levels of ERK5 were significantly enhanced in human platelets stimulated with botrocetin/VWF or ristocetin/VWF. The ERK5 inhibitor XMD8-92 suppressed the second wave of human platelet aggregation induced by botrocetin/VWF or ristocetin/VWF and inhibited human platelet adhesion on immobilized VWF under shear stress. Casein kinase II (CKII) was identified as an ERK5-associated protein in human platelets. The CKII inhibitor TBB, similar to the ERK5 inhibitor XMD8-92, specifically restrained PTEN phosphorylation, therefore suppressing Akt phosphorylation in human platelets treated with botrocetin/VWF. Conclusion ERK5 associates with CKII to play essential roles in GPIb-IX-mediated platelet activation via the PTEN/PI3K/Akt pathway.

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

Cited by 40 publications

References 52 publications

Integrated transcriptomic and proteomic analysis identifies protein kinase CK2 as a key signaling node in an inflammatory cytokine network in ovarian cancer cells

Integrated transcriptomic and proteomic analysis identifies protein kinase CK2 as a key signaling node in an inflammatory cytokine network in ovarian cancer cells

The Selectivity of CK2 Inhibitor Quinalizarin: A Reevaluation

Extracellular signal‐regulated kinase 5 associates with casein kinase II to regulate GPIb‐IX‐mediated platelet activation via the PTEN/PI3K/Akt pathway

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