Role of protein kinase CK2 in antitumor drug resistance

Borgo, Christian; Ruzzene, Maria

doi:10.1186/s13046-019-1292-y

Cited by 87 publications

(71 citation statements)

References 132 publications

(166 reference statements)

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“…Many features defining this enzyme at the molecular level cannot be covered in this review. However, excellent reviews exploring different aspects of this protein kinase have been published; some are cited here [ 132 , 133 , 134 , 135 , 136 , 137 , 138 ].…”

Section: The Role Of Ck2 In Lipid Metabolismmentioning

confidence: 99%

Role of Protein Kinase CK2 in Aberrant Lipid Metabolism in Cancer

Guerra

Issinger

2020

Pharmaceuticals

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Uncontrolled proliferation is a feature defining cancer and it is linked to the ability of cancer cells to effectively adapt their metabolic needs in response to a harsh tumor environment. Metabolic reprogramming is considered a hallmark of cancer and includes increased glucose uptake and processing, and increased glutamine utilization, but also the deregulation of lipid and cholesterol-associated signal transduction, as highlighted in recent years. In the first part of the review, we will (i) provide an overview of the major types of lipids found in eukaryotic cells and their importance as mediators of intracellular signaling pathways (ii) analyze the main metabolic changes occurring in cancer development and the role of oncogenic signaling in supporting aberrant lipid metabolism and (iii) discuss combination strategies as powerful new approaches to cancer treatment. The second part of the review will address the emerging role of CK2, a conserved serine/threonine protein kinase, in lipid homeostasis with an emphasis regarding its function in lipogenesis and adipogenesis. Evidence will be provided that CK2 regulates these processes at multiple levels. This suggests that its pharmacological inhibition combined with dietary restrictions and/or inhibitors of metabolic targets could represent an effective way to undermine the dependency of cancer cells on lipids to interfere with tumor progression.

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Section: The Role Of Ck2 In Lipid Metabolismmentioning

confidence: 99%

Role of Protein Kinase CK2 in Aberrant Lipid Metabolism in Cancer

Guerra

Issinger

2020

Pharmaceuticals

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“…Besides, it has been proposed that CK2 may impair caspase activation, i.e., due to similarity between the kinase consensus sequence and the caspase recognition motif, CK2-mediated phosphorylation of several caspase substrates could protect them from cleavage [24]. Finally, a role of CK2 in multidrug resistance has recently been reviewed, highlighting its involvement in promoting DNA repair and drug efflux, as well as in sustaining diverse signalling pathways to escape cell death [25].…”

Section: Introductionmentioning

confidence: 99%

Role of CK2 inhibitor CX-4945 in anti-cancer combination therapy – potential clinical relevance

et al. 2020

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Background Protein kinase CK2 inhibition has long been considered as an attractive anti-cancer strategy based on the following considerations: CK2 is a pro-survival kinase, it is frequently over-expressed in human tumours and its over-expression correlates with a worse prognosis. Preclinical evidence strongly supports the feasibility of this target and, although dozens of CK2 inhibitors have been described in the literature so far, CX-4945 (silmitasertib) was the first that entered into clinical trials for the treatment of both human haematological and solid tumours. However, kinase inhibitor monotherapies turned out to be effective only in a limited number of malignancies, probably due to the multifaceted causes that underlie them, supporting the emerging view that multi-targeted approaches to treat human tumours could be more effective. Conclusions In this review, we will address combined anti-cancer therapeutic strategies described so far which involve the use of CX-4945. Data from preclinical studies clearly show the ability of CX-4945 to synergistically cooperate with different classes of anti-neoplastic agents, thereby contributing to an orchestrated anti-tumour action against multiple targets. Overall, these promising outcomes support the translation of CX-4945 combined therapies into clinical anti-cancer applications.

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“…Moreover, several evidences support a role for CK2 in the processes directly responsible for drug resistance, such as drug efflux and DNA repair. CK2 intervenes in signaling pathways which are crucial to evade drug response (i.e., PI3K, phosphoinositide 3-kinase/AKT/PTEN, NF-κB, β-catenin, hedgehog signaling, and p53), and controls the activity of chaperone machineries fundamental in resistant cells [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

Wińska

Karatsai

Staniszewska

et al. 2020

IJMS

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Background: The combination effect of 5-fluorouracil (5-FU) with either CX-4945 or a new inhibitor of protein kinase CK2, namely 14B (4,5,6,7-tetrabromo-1-(3-bromopropyl)-2-methyl-1H-benzimidazole), on the viability of MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines was studied. Methods: Combination index (CI) values were determined using an MTT-based assay and the Chou-Talalay model. The effect of the tested drug combinations on pro-apoptotic properties and cell cycle progression was examined using flow cytometry. The activation of FAK, p38 MAPK, and ERK1/2 kinases and the expression of selected pro-apoptotic markers in MDA-MB-231 cell line after the combined treatment were evaluated by the western blot method. Confocal microscopy was used to examine actin network in MDA-MB-231. Results: Our results showed that a synergistic effect (CI < 1) occurred in MDA-MB-231 after treatment with both combinations of 5-FU with 14B or CX-4945, whereas the combination of 5-FU and 14B evoked an antagonistic effect in MCF-7. We conclude that the synergistic interactions (CI < 1) observed for both the combinations of 5-FU and 14B or CX-4945 in MDA-MB-231 correlated with an activation of p38 MAPK, inhibition of FAK, increased expression of apoptogenic markers, prolongation of S-phase of cell cycle, and destabilization of actin network. Conclusions: The obtained results support the recent observation that CK2 inhibitors can improve 5-FU-based anticancer therapy and FAK kinase can be an attractive molecular target in breast cancer therapy.

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Role of protein kinase CK2 in antitumor drug resistance

Cited by 87 publications

References 132 publications

Role of Protein Kinase CK2 in Aberrant Lipid Metabolism in Cancer

Role of Protein Kinase CK2 in Aberrant Lipid Metabolism in Cancer

Role of CK2 inhibitor CX-4945 in anti-cancer combination therapy – potential clinical relevance

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

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