CK2 and the Hallmarks of Cancer

Firnau, May-Britt; Brieger, Angela

doi:10.3390/biomedicines10081987

Cited by 20 publications

(33 citation statements)

References 572 publications

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“…Treatment with AB668 strongly impacted cancer cell viability resulting in apoptotic cell death, while sparing healthy cells. A long-held view has suggested that malignant cells are dependent upon sustained CK2 signaling for survival thereby exhibiting an exquisite sensitivity to CK2 inhibition (Ruzzene et al, 2010; Roffey et al, 2021; Firnau et al, 2022). Conversely, non-cancer cells are more resistant to induction of cell death on downregulation of CK2 activity, which is the expected basis for safely using a pharmacological chemical inhibitor.…”

Section: Discussionmentioning

confidence: 99%

“…The higher sensitivity of cancer cells to CK2 inhibition, as compared to their healthy counterparts, led to the hypothesis of a “non-oncogenic” CK2 addiction of cancer cells (Luo et al, 2009; Ruzzene et al, 2010). Compiling evidence from the literature suggests that CK2 modulates all hallmarks of cancer (Firnau et al, 2022). Consequently, CK2 is considered as a “master regulator” and a promising therapeutic target to treat different human tumors (Roffey et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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AB668, a novel highly selective protein kinase CK2 inhibitor with a distinct anti-tumor mechanism as compared to CX-4945 and SGC-CK2-1

Bancet

Frem

Jeanneret

et al. 2022

Preprint

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Although the involvement of protein kinase CK2 in cancer is well-documented, there is a need for selective CK2 inhibitors suitable for investigating CK2 specific roles in cancer-related biological pathways and further explore its therapeutic potential. Here we have discovered AB668, a new bivalent inhibitor that binds both at the ATP site and an allosteric αD pocket unique to CK2. The molecule inhibits CK2 activity with an outstanding selectivity over other kinases. Using caspase activation assay, live-cell imaging and transcriptomic analysis, we have compared the effects of this bivalent inhibitor to the non-selective ATP-competitive inhibitor CX-4945 that reached clinic and to the selective ATP-competitive SGC-CK2-1 molecule. Our results show that in contrast to CX-4945 or SGC-CK2-1, AB668 has a distinct mechanism of action regarding its anti-cancer activity, inducing apoptotic cell death and stimulating distinct biological pathways in several cancer cell lines while sparing healthy cells. Our data suggest that targeting a cryptic CK2 αD pocket validates an allosteric approach to targeting CK2 and provides a starting point for creating drug-like CK2 inhibitors for aggressive cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

AB668, a novel highly selective protein kinase CK2 inhibitor with a distinct anti-tumor mechanism as compared to CX-4945 and SGC-CK2-1

Bancet

Frem

Jeanneret

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Furthermore, phosphorylation of FADD at Ser200 indicated its nuclear localization, which is influenced by Casein kinase 2 (CK2). Elevated level of CK2 have been detected in malignant cells and various types of cancers, such as lung, colon, breast, ovarian, pancreatic, and prostate cancer [ 13 , 63 ]. Interestingly, phosphorylation of FADD at serine 194 mediates the nuclear localization of FADD for genomic surveillance [ 54 ].…”

Section: Structure and Cellular Localization Of Fas-associated Death ...mentioning

confidence: 99%

Cellular Dynamics of Fas-Associated Death Domain in the Regulation of Cancer and Inflammation

Ranjan,

Pathak

2024

IJMS

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Fas-associated death domain (FADD) is an adaptor protein that predominantly transduces the apoptosis signal from the death receptor (DR) to activate caspases, leading to the initiation of apoptotic signaling and the coordinated removal of damaged, infected, or unwanted cells. In addition to its apoptotic functions, FADD is involved in signaling pathways related to autophagy, cell proliferation, necroptosis, and cellular senescence, indicating its versatile role in cell survival and proliferation. The subcellular localization and intracellular expression of FADD play a crucial role in determining its functional outcomes, thereby highlighting the importance of spatiotemporal mechanisms and regulation. Furthermore, FADD has emerged as a key regulator of inflammatory signaling, contributing to immune responses and cellular homeostasis. This review provides a comprehensive summary and analysis of the cellular dynamics of FADD in regulating programmed cell death and inflammation through distinct molecular mechanisms associated with various signaling pathways.

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“…Among these kinases, Casein kinase 2 (CK2) is a conserved serine/threonine kinase in many species and has recently gained attention due to its involvement in many cellular processes, such as cell growth, death, and migration. CK2 is known to regulate diverse signaling pathways by phosphorylating a wide range of protein substrates involved in cell adhesion, cytoskeletal organization, and EMT [ 30 , 31 ]. CK2-mediated phosphorylation of key substrates has been implicated as a critical step in metastasis by modulating activities of transcription factors, cell adhesion molecules, and components of signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

CK2α-mediated phosphorylation of GRP94 facilitates the metastatic cascade in triple-negative breast cancer

Kim,

Hong

2024

Cell Death Discov.

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Distant metastasis is a significant hallmark affecting to the high death rate of patients with triple-negative breast cancer (TNBC). Thus, it is crucial to identify and develop new therapeutic strategies to hinder cancer metastasis. While emerging studies have hinted a pivotal role of glucose-regulated protein 94 (GRP94) in tumorigenesis, the exact biological functions and molecular mechanisms of GRP94 in modulating cancer metastasis remain to be elucidated. Our study demonstrated an increased expression of GRP94 in TNBC correlated with metastatic progression and unfavorable prognosis in patients. Functionally, we identified that GRP94 depletion significantly diminished TNBC tumorigenesis and subsequent lung metastasis. In contrast, GRP94 overexpression exacerbated the invasiveness, migration, and lung metastasis of non-TNBC cells. Mechanistically, we found that casein kinase 2 alpha (CK2α) active in advanced breast cancer phosphorylated GRP94 at a conserved serine 306 (S306) residue. This phosphorylation increased the stability of GRP94 and enhanced its interaction with LRP6, leading to activation of canonical Wnt signaling. From a therapeutic standpoint, we found that benzamidine, a novel CK2α inhibitor, effectively suppressed GRP94 phosphorylation, LRP6 stabilization, and metastasis of TNBC. Our results point to the critical role of CK2α-mediated GRP94 phosphorylation in TNBC metastasis through activation of Wnt signaling, highlighting GRP94 as a therapeutic target to impede TNBC metastasis.

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CK2 and the Hallmarks of Cancer

Cited by 20 publications

References 572 publications

AB668, a novel highly selective protein kinase CK2 inhibitor with a distinct anti-tumor mechanism as compared to CX-4945 and SGC-CK2-1

AB668, a novel highly selective protein kinase CK2 inhibitor with a distinct anti-tumor mechanism as compared to CX-4945 and SGC-CK2-1

Cellular Dynamics of Fas-Associated Death Domain in the Regulation of Cancer and Inflammation

CK2α-mediated phosphorylation of GRP94 facilitates the metastatic cascade in triple-negative breast cancer

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