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

Zhang, Xiaolei; Yang, Xiao; Yang, Chengying; Yuan, Wenwen; Deng, Xiaheng; Cheng, Yidong; Yang, Haiwei; Tao, Jun; Lü, Qiang

doi:10.18632/oncotarget.13571

Cited by 25 publications

(31 citation statements)

References 36 publications

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“…Downregulation of protein kinase CK2 induced the senescent phenotype in human diploid fibroblast IMR-90 cells [ 20 ], and decreased androgen receptor nuclear translocation, which led to a reduced expression of genes required for prostate cancer cell proliferation [ 21 ]. CX-4945 has also been shown to decrease the survival of many cancer cell types including bladder [ 22 ], hematological [ 23 , 24 ], prostate [ 25 ], and breast cancer cells [ 26 ]. CX-4945 up to 10 µM showed an inhibition on Akt phosphorylation in prostate cancer, PC3 cells, and [ 27 ] non-small cell lung cancer cells, H1299, Calu-1, and H358 [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism

Lertsuwan

Sawasdichai

et al. 2018

Cancers

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Cholangiocarcinoma is a disease with a poor prognosis and increasing incidence and hence there is a pressing unmet clinical need for new adjuvant treatments. Protein kinase CK2 (previously casein kinase II) is a ubiquitously expressed protein kinase that is up-regulated in multiple cancer cell types. The inhibition of CK2 activity using CX-4945 (Silmitasertib) has been proposed as a novel treatment in multiple disease settings including cholangiocarcinoma. Here, we show that CX-4945 inhibited the proliferation of cholangiocarcinoma cell lines in vitro. Moreover, CX-4945 treatment induced the formation of cytosolic vacuoles in cholangiocarcinoma cell lines and other cancer cell lines. The vacuoles contained extracellular fluid and had neutral pH, features characteristic of methuosis. In contrast, simultaneous knockdown of both the α and α′ catalytic subunits of protein kinase CK2 using small interfering RNA (siRNA) had little or no effect on the proliferation of cholangiocarcinoma cell lines and failed to induce the vacuole formation. Surprisingly, low doses of CX-4945 increased the invasive properties of cholangiocarcinoma cells due to an upregulation of matrix metallopeptidase 7 (MMP-7), while the knockdown of CK2 inhibited cell invasion. Our data suggest that CX-4945 inhibits cell proliferation and induces cell death via CK2-independent pathways. Moreover, the increase in cell invasion brought about by CX-4945 treatment suggests that this drug might increase tumor invasion in clinical settings.

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Section: Introductionmentioning

confidence: 99%

CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism

Lertsuwan

Sawasdichai

et al. 2018

Cancers

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“…The expression level of CK2α was defined as follows: ‘‘-” (negative, score 0), ‘‘+” (weakly positive, score 1–3), ‘‘++” (positive, score 4–6) or ‘‘+++” (strong positive, score 7–9). CK2α protein expression in EOC tissues was divided into two groups: low CK2α expression group (CK2α‘‘-”or CK2α‘‘+”) and high CK2α expression group (CK2α‘‘++” or CK2α‘‘+++”) [32, 33]. …”

Section: Methodsmentioning

confidence: 99%

Increased expression of protein kinase CK2α correlates with poor patient prognosis in epithelial ovarian cancer

Wang

He³

et al. 2017

PLoS ONE

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Epithelial ovarian cancer (EOC) is one of the deadly gynecological malignancies. The function of protein kinase CK2α (CK2α) in EOC is still unknown. Our study aimed to investigate the relationship between the protein expression of CK2α and the tumor progression, the prognosis of human EOC. In this study, we analyzed the expression levels of CK2α through Western blot, using EOC cell lines like A2780, HO8910, COV644, OVCAR3, SKOV3, and the primary normal ovarian surface epithelial (NOSE) cells. Furthermore, OVCAR3 and SKOV3 EOC cells were employed as a cellular model to study the role of CK2α on cell growth, migration, invasion, apoptosis, and cell cycle distribution. In addition, we investigated CK2α protein expression in tumor tissues from patients with EOC by immunohistochemistry and analyzed the association between CK2α expression and clinicopathologic parameters and prognosis of EOC patients. And we found that compared with NOSE cells, CK2α protein expression was increased in A2780, HO8910, OVCAR3, and SKOV3 ovarian cancer cell lines. Decreased CK2α expression suppressed OVCAR3 and SKOV3 cell growth and induced more apoptosis. CK2α knockdown using specific siRNAs inhibited migration and invasion ability of OVCAR3 and SKOV3 cells. In addition, high CK2α protein expression was found in 68.4% (80/117) of EOC patients. Increased CK2α expression of was significantly correlated with FIGO staging and peritoneal cytology. Patients with higher CK2α expression had a significantly poorer overall survival compared with those with lower CK2α expression. Multi-variate Cox regression analysis proved that increased CK2α expression was an independent prognostic marker for EOC. Taken together, our data displayed that CK2α may play a role in tumor aggressive behavior of EOC and could be used as a marker for predicting prognosis of EOC patient. High CK2α expression might predict poor patient survival.

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“…CK2α, a catalytic subunit of CK2, has a significant serine/threonine kinase activity and even been considered to be significant in numerous key biological processes such as cell proliferation, differentiation and apoptosis [ 13 – 16 ]. What’s more, CK2α participates in development and progression of diseases including angiogenesis, glomerulonephritis, organogenesis and cancer [ 17 – 20 ]. Our previous study shows that activated CK2α provokes inflammatory nuclear factor NF-κB through interacting with IκB to increase its degradation, upregulating expressions of inflammatory fibrotic factors including FN and ICAM-1 under diabetic state [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Sphingosine kinase 1 mediates diabetic renal fibrosis via NF-κB signaling pathway: involvement of CK2α

Huang

Chen

et al. 2017

Oncotarget

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Sphingosine kinase 1 (SphK1) plays a pivotal role in regulating diabetic renal fibrotic factors such as fibronectin (FN) and intercellular adhesion molecule-1 (ICAM-1). Especially, activation of SphK1 is closely linked to the body inflammatory reaction. Casein kinase 2α subunit (CK2α), a protein kinase related to inflammatory reaction, influences diabetic renal fibrosis and expressions of FN and ICAM-1 via NF-κB pathway. However, the mechanism by which SphK1 mediates diabetic renal fibrosis has not yet fully elucidated. The current study is aimed to investigate if SphK1 mediates diabetic renal fibrotic pathological process via inflammatory pathway and activation of CK2α. The following findings were observed: (1) Expressions of SphK1 were upregulated in kidneys of diabetic mice and rats; (2) Knockdown of SphK1 expression suppressed high glucose (HG)-induced NF-κB nuclear translocation and expressions of FN and ICAM-1; (3) Compared with C57 diabetic mice, SphK1-/- diabetic mice exhibited less renal fibrotic lesions, FN accumulation and NF-κB nuclear accumulation in glomeruli of kidneys; (4) SphK1 mediated phosphorylation of CK2α, while CK2α knockdown depressed SphK1-induced activation of NF-κB pathway. This study indicates the essential role of SphK1 in regulating activation of CK2α and diabetic renal fibrotic pathological process via NF-κB.

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

Cited by 25 publications

References 36 publications

CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism

CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism

Increased expression of protein kinase CK2α correlates with poor patient prognosis in epithelial ovarian cancer

Sphingosine kinase 1 mediates diabetic renal fibrosis via NF-κB signaling pathway: involvement of CK2α

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