Oncogenic potential of <scp>CK</scp>2α and its regulatory role in <scp>EGF</scp>‐induced <scp>HDAC</scp>2 expression in human liver cancer

Kim, Hyung S.; Chang, Young Gyoon; Bae, Hyun Jin; Eun, Jung Woo; Shen, Qingyu; Park, Se J.; Shin, Woo Chan; Lee, Eun K.; Park, Soha; Ahn, Young Min; Park, Won S; Lee, Jung Y.; Nam, Suk Woo

doi:10.1111/febs.12652

Cited by 36 publications

(28 citation statements)

References 22 publications

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“…Protein kinase CK2α, one isoform of the catalytic subunit of serine/threonine protein kinase CK2, has been demonstrated to be overexpressed in various malignancies [26–28]. However, its underlying role in bladder cancer remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Targeting protein kinase CK2 suppresses bladder cancer cell survival via the glucose metabolic pathway

Zhang

Yang

et al. 2016

Oncotarget

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Casein kinase 2 (CK2) is a constitutively active serine/threonine kinase that promotes cell proliferation and resists apoptosis. Elevated CK2 expression has been demonstrated in several solid tumors. The expression of CK2α in bladder cancer was elevated in tumor tissues compared with that in adjacent normal tissues. Amplified expression of CK2α was highly correlated with histological grade in bladder cancer(P = 0.024). Knockdown of CK2α in bladder cancer cell lines resulted in a reduction in tumor aerobic glycolysis, accompanied with lower phosphorylated AKT. Moreover, low CK2α levels suppressed cell growth, and similar results could be reproduced after treatment with CX-4945 with a dose-dependent response. CX-4945 inhibited migration and induced apoptosis. Furthermore, knockdown of CK2α decreased the tumorigenicity of bladder cancer cells in vivo. This study is the first to report that CK2 increases glucose metabolism in human bladder cancer. Blocking CK2 function may provide novel diagnostic and potential therapeutic.

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Section: Discussionmentioning

confidence: 99%

Targeting protein kinase CK2 suppresses bladder cancer cell survival via the glucose metabolic pathway

Zhang

Yang

et al. 2016

Oncotarget

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“…Furthermore, we investigated the serum proteome of EGF-tumour-bearing mice to obtain information on disease-regulated proteins and to search for novel biomarkers at different stages of disease [7]. Note, a regulatory loop was proposed whereby EGF induces transcriptional activation of HDAC2 by CK2Α/AKT activation in liver cancer cells [8]. Additionally, inhibition of EGFR in different animal models by Erlotinib was shown to attenuate liver fibrosis and the development of hepatocellular carcinoma [9] thus suggesting new therapeutic intervention strategies in the prevention of HCC.…”

Section: Introductionmentioning

confidence: 99%

Proteome mapping of epidermal growth factor induced hepatocellular carcinomas identifies novel cell metabolism targets and mitogen activated protein kinase signalling events

2015

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BackgroundHepatocellular carcinoma (HCC) is on the rise and the sixth most common cancer worldwide. To combat HCC effectively research is directed towards its early detection and the development of targeted therapies. Given the fact that epidermal growth factor (EGF) is an important mitogen for hepatocytes we searched for disease regulated proteins to improve an understanding of the molecular pathogenesis of EGF induced HCC. Disease regulated proteins were studied by 2DE MALDI-TOF/TOF and a transcriptomic approach, by immunohistochemistry and advanced bioinformatics.ResultsMapping of EGF induced liver cancer in a transgenic mouse model identified n = 96 (p < 0.05) significantly regulated proteins of which n = 54 were tumour-specific. To unravel molecular circuits linked to aberrant EGFR signalling diverse computational approaches were employed and this defined n = 7 key nodes using n = 82 disease regulated proteins for network construction. STRING analysis revealed protein-protein interactions of > 70% disease regulated proteins with individual proteins being validated by immunohistochemistry. The disease regulated network proteins were mapped to distinct pathways and bioinformatics provided novel insight into molecular circuits associated with significant changes in either glycolysis and gluconeogenesis, argine and proline metabolism, protein processing in endoplasmic reticulum, Hif- and MAPK signalling, lipoprotein metabolism, platelet activation and hemostatic control as a result of aberrant EGF signalling. The biological significance of the findings was corroborated with gene expression data derived from tumour tissues to evntually define a rationale by which tumours embark on intriguing changes in metabolism that is of utility for an understanding of tumour growth. Moreover, among the EGF tumour specific proteins n = 11 were likewise uniquely expressed in human HCC and for n = 49 proteins regulation in human HCC was confirmed using the publically available Human Protein Atlas depository, therefore demonstrating clinical significance.ConclusionNovel insight into the molecular pathogenesis of EGF induced liver cancer was obtained and among the 37 newly identified proteins several are likely candidates for the development of molecularly targeted therapies and include the nucleoside diphosphate kinase A, bifunctional ATP-dependent dihydroyacetone kinase and phosphatidylethanolamine-binding protein1, the latter being an inhibitor of the Raf-1 kinase.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1312-z) contains supplementary material, which is available to authorized users.

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“…This is not the first time that CK2 could be viewed as a prognostic marker for cancer. Elevated levels of CK2α corresponded with a worse prognosis in glioblastoma [7], breast [18], ovarian [18], gastric cancer [19,20], renal clear cell carcinoma [21], AML [20,22], liver cancer [23,24], and sarcomas [20]. High expression of CK2β lead to a poor prognosis in lung adenocarcinoma [18], breast [18], gastric cancer [20,25], and head and neck cancer [20].…”

Section: Ck2 and Mb Clinical Relevancementioning

confidence: 99%

Casein kinase 2 inhibition sensitizes medulloblastoma to temozolomide

et al. 2019

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Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Since surviving patients experience severe neurocognitive disabilities, better and more effective treatments are needed to enhance their quality of life. Casein kinase 2 (CK2) is known to regulate cell growth and survival in multiple cancers; however, the role of CK2 in MB is currently being studied. In this study, we verified the importance of CK2 in MB tumorigenesis and discovered that inhibition of CK2 using the small molecule inhibitor, CX-4945, can sensitize MB cells to a well-known and tolerated chemotherapeutic, temozolomide (TMZ). To study the role of CK2 in MB we modulated CK2 expression in multiple MB cells. Exogenous expression of CK2 enhanced cell growth and tumor growth in mice, while depletion or inhibition of CK2 expression decreased MB tumorigenesis. Treatment with CX-4945 reduced MB growth and increased apoptosis. We conducted a highthroughput screen where 4000 small molecule compounds were analyzed to identify compounds that increased the antitumorigenic properties of CX-4945. TMZ was found to work synergistically with CX-4945 to decrease cell survival and increase apoptosis in MB cells. O-6-methylguanine-DNA methyltransferase (MGMT) activity is directly correlated to TMZ sensitivity. We found that loss of CK2 activity reduced β-catenin expression, a known MGMT regulator, which in turn led to a decrease in MGMT expression and an increased sensitivity to TMZ. Our findings show that CK2 is important for MB maintenance and that treatment with CX-4945 can sensitize MB cells to TMZ treatment.

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Oncogenic potential of CK2α and its regulatory role in EGF‐induced HDAC2 expression in human liver cancer

Cited by 36 publications

References 22 publications

Targeting protein kinase CK2 suppresses bladder cancer cell survival via the glucose metabolic pathway

Targeting protein kinase CK2 suppresses bladder cancer cell survival via the glucose metabolic pathway

Proteome mapping of epidermal growth factor induced hepatocellular carcinomas identifies novel cell metabolism targets and mitogen activated protein kinase signalling events

Casein kinase 2 inhibition sensitizes medulloblastoma to temozolomide

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