Research ArticleExperimental Studies

The Casein Kinase 2 Inhibitor CX-4945 Promotes Cholangiocarcinoma Cell Death Through PLK1

DA SOL LEE, SEONMIN LEE, CHORONG KIM, DANBEE KIM, KYU-PYO KIM and CHANGHOON YOO
Anticancer Research July 2022, 42 (7) 3435-3443; DOI: https://doi.org/10.21873/anticanres.15830

Abstract

Background/Aim: Casein Kinase 2 (CK2) is a prosurvival protein kinase involved in cell growth/proliferation through the regulation of the cell cycle and apoptosis. CK2 is over-expressed in various cancers, which correlates with a poor prognosis. This study examined the anti-cancer effects of silmitasertib (CX-4945), a CK2 inhibitor, on cholangiocarcinoma (CCA) cells. Materials and Methods: The effects of CX-4945 on cell viability, cell cycle arrest, and apoptosis in the human cholangiocarcinoma cell lines TFK-1 and SSP-25 were evaluated. Alterations in posttranslational modifications and the levels of cell cycle regulators including p21, Polo-like kinase 1 (PLK1), andp53 were assessed by western blotting. Apoptotic responses were examined using Propidium iodine/Annexin V staining. Results: TFK-1 and SSP-25 cells exposed to CX-4945 showed morphologic changes and a more than 50% decrease in cell viability (p<0.05). Cell cycle arrest at the G2 phase was detected following an increase in phosphorylated PLK1 and p21. Furthermore, phospho-PLK1 induced the degradation of p53, which led to the dissociation of Bax from Bcl-xL. The cleavage of Caspase3 and PARP were also induced by CX-4945 treatment. Conclusion: CX-4945 induces cell cycle arrest and cell death in cholangiocarcinoma cells via the regulation of PLK1 and p53. This may provide a novel therapeutic strategy for advanced cholangiocarcinoma.

Key Words:

Cholangiocarcinoma (CCA) is the malignancy of the biliary tree and the second most common primary liver cancer, with an increasing incidence worldwide (1). The prognosis of CCA is dismal as the median overall survival is less than 1 year (2). The molecular mechanisms underlying the malignant phenotype of CCA are still poorly understood. Currently, progressive CCA is treated using gemcitabine and cisplatin, but it is still not a curative solution (3). Although fibroblast growth factor receptor (FGFR) and isocitrate dehydrogenase (IDH)-1 inhibitors have been approved for both FGFR2 fusion gene and IDH-1 mutated CCA, they benefit only up to 20% of CCA patients (3). Further investigations to develop novel targeted therapies for CCA are thus necessary.

Casein kinase 2 (CK2) is a constitutively active serine/ threonine-protein kinase comprising two catalytic subunits (α or isoform α’) and two regulatory subunits (β) (4). CK2 regulates a large number of signaling pathways involved in diverse intracellular events, including cell proliferation, apoptosis, and cell cycle. CK2 over-expression is also observed in a variety of cancers and positively correlates with a poor prognosis (4). In various animal models for multiple cancer types, the inhibition of CK2 has shown a promising in vitro and in vivo anti-cancer efficacy (5, 6). An example of this is CX-4945, a potent and selective inhibitor of CK2, which has demonstrated anti-proliferative effects in preclinical models of CCA (5-8).

Polo-like kinase 1 (PLK1) is a mitotic kinase that regulates the cell cycle and its over-expression has been associated with malignant transformation (9). Therefore, we hypothesized that PLK1 may have a role in CK2-induced cell death. In the current study, we investigated the anti-tumor efficacy of CX4945 in CCA cell lines, and the possible role of PLK1 in the CK2 inhibitor-induced CCA cell death.

Materials and Methods

Cell lines and cell culture. The human CCA cell lines TFK-1 and SSP-25 were obtained from the Asan Preclinical Evaluation Center for Cancer TherapeutiX, Asan Medical Center, Seoul, Republic of Korea. Both cell lines were cultured in 100 mm3 dishes to 90% confluency in RPMI medium 1640 (Gibco, Grand Island, NY, USA) supplemented with 10% fetal bovine serum (WELGENE,Gyeongsan, Republic of Korea) and 1% penicillin-streptomycin (Gibco). All cells were incubated in a humidified incubator at 37°C with 5% CO2.

Cell survival assay. For cell survival assays, the cells were seeded at 2×103 cells/well in 96-well plates and exposed to 5, 10, and 15 μM of CX-4945 for 24 and 48 h. Following this treatment, 15 μl of cell Glo-titer solution (Promega, Madison, WI, USA) was added to each well, and the cells were then incubated for 10 min at room temperature to stabilize the luminescent signal. After this incubation, 100 μl was aliquots were transferred to a white 96-well plate and read using a luminescence reader (VICTOR X2; PerkinElmer, Waltham, MA, USA). The IC50 values were then estimated using GraphPad Prism 5 software (GraphPad, San Diego, CA, USA).

Cell cycle analysis. For cell cycle analysis, the cells were fixed with 70% ethanol at –20°C and then stained with FxCycle PI/RNase solution (Invitrogen, Waltham, MA, USA). The samples were then analyzed using a FACS Canto II flow cytometer (BD Biosciences, San Jose, CA, USA) and FlowJo V10 software (FlowJo, Jackson County, OR, USA). The FACS Canto II was operated by the Flow Cytometry Core Facility, Research Development Support Center, Asan Medical Center.

Apoptosis analysis. Apoptosis was analyzed by flow cytometry using a commercially available Annexin V-FITC kit (Miltenyi Biotec, Bergisch Gladbach, North Rhine-Westphalia, Germany) in accordance with the manufacturer’s instructions. In brief, the cells were washed with 1×binding buffer after centrifugation and complete aspiration of the supernatant. Following a further centrifugation, the cell pellet was resuspended in 100 μl of 1×binding buffer with the addition of 10 μl of annexin V-FITC, and then incubated at room temperature for 15 min in the dark. The cells were again washed with 1×binding buffer and analyzed by flow cytometry.

Co-immunoprecipitation and western blotting. For immunoprecipitation and immunoblotting experiments, the TFK-1 and SSP-25 cells were first lysed with a commercial whole-cell lysis cell extraction buffer (Invitrogen) containing a protease inhibitor cocktail (Roche, Mannheim, Germany). The lysates (1 mg in total) were then incubated with anti-PLK1 or anti-p53 antibodies to form immunocomplexes which were precipitated overnight with Pierce Protein A/G agarose (Thermo Scientific, Waltham, MA, USA) at 4°C and then pelleted by centrifugation at 15,000 rpm for 10 min. The immunoprecipitates were washed three times with lysis buffer at 4°C and subjected to western blotting as follows.

For western blotting analysis, the proteins were loaded into the wells of NuPAGE™ 4-12% Bis-Tris Protein Gels (Invitrogen) and separated using SDS-PAGE in NuPAGE™ MES SDS Running Buffer (Invitrogen) and transferred onto polyvinylidene difluoride membranes (Invitrogen). The membranes were blocked with 5% BSA in PBST for 1 h at room temperature and incubated with a primary antibody at 4°C overnight. The following primary antibodies were used: casein kinase 2α (Thermo Scientific), phospho-casein kinase 2α (Sigma, Burlington, MA, USA), Cleaved Caspase-3 (Cell Signaling, Danvers, MA, USA), Cleaved PARP (Cell Signaling), Bax (Cell Signaling), Bcl-xL (Abcam, Cambridge, UK), p21 (Abcam), phospho-p21 (Invitrogen), p53 (Cell Signaling), phospho-p53 (Cell Signaling), PLK1 (NOVUS, Centennial, CO, USA), phospho-PLK1 (Cell Signaling), Ubiquitination (Abcam), and β-actin (Sigma). The membranes were developed using SuperSignal West Femto Stable Peroxide Buffer (Thermo Scientific) to enhance the signals and then detected by using a Chemiluminescence Imaging System (ATTO, Tokyo, Japan).

Results

CX-4945 decreases the viability of CCA cells. We first examined the effects of CX-4945 on CK2 at the protein level in both the TFK-1 and SSP-25 cell lines. Although there were no significant changes in the overall total-form CK2α levels, the levels of the active phospho-form of CK2α were decreased following exposure to CX-4945 (Figure 1A). We further observed dose-dependent morphological changes following CX-4945 treatment. As the CX-4945 concentration increased, apoptotic morphology was observed (Figure 1B). Moreover, CX-4945 treatments lowered the viability of the CCA cell lines (Figure 1C).

Figure 1.
Figure 1.

CX-4945 reduces the viability of cholangiocarcinoma cells. (A) CCA cells were treated with different concentrations of CX-4945 for 48 h and then analyzed by western blotting. (B) Cell morphologies were observed under an optical microscope. (C) CCA cells were treated with the indicated doses of CX-4945 for 24 and 48 h (*p<0.05, **p<0.01, ***p<0.001). Cell viability was then examined using a Glo-titer assay.

CX-4945 triggers apoptotic cell death. FACS analysis showed that treatment with CX-4945 increased both early (Q4) and late (Q2) apoptosis in the TFK-1 and SSP-25 cell lines (Figure 2A). The levels of cleaved Caspase-3 and PARP, apoptosis protein markers, were also increased in both cell lines by CX-4945 treatment (Figure 2B).

Figure 2.
Figure 2.

CX-4945 triggers apoptosis in cholangiocarcinoma cells. (A) Apoptosis was assessed by Annexin V-FITC/PI staining and flow cytometry. (B) Western blotting analysis of apoptotic proteins in CCA cells treated with CX-4945 for 48 h.

CX-4945 induces apoptosis through free Bax. Apoptosis is a well-controlled cell death process involved with p53 and those of the Bcl-2 family (10-12). In particular, cytoplasmic p53 has a pivotal role in apoptosis regulation (10). Cytoplasmic p53 initiates apoptosis by inducing mitochondrial potential disruption following the dissociation of Bax from Bcl-xL/Bax complex (10-13).

We analyzed the physical interactions between p53, Bcl-xL, and Bax, under CX-4945 treatment. The interaction between p53 and Bcl-xL was increased by CX-4945 exposure in a dose-dependent manner (Figure 3A and B). However, the interaction of Bax with Bcl-xL was decreased (Figure 3A). The free Bax may be transferred to mitochondria and trigger apoptosis (10) through caspase activation as shown in Figure 2B. Because CX-4945 triggered apoptosis through free Bax by decreasing the physical interaction between p53 with Bcl-xL (12, 13). CX-4945 reduced both the phospho- and totalforms of p53 in a dose-dependent manner (Figure 3C). In addition, the phospho-form of p21 was significantly decreased by CX-4945, while the total-form of p21 was elevated, indicating cell cycle arrest (Figure 3D).

Figure 3.
Figure 3.

CX-4945 dissociates Bax from Bcl-xL, which is regulated by p53 and p21. CCA cells were treated with CX-4945 (5 and 15 μM) for 48 h. (A, B) CX-4945 regulates complex formation between Bax and Bcl-xL. Bax is activated by ubiquitinated p53 and induces caspase activation in the TFK-1 and SSP-25 CCA cell lines. (C, D) Effects of CX-4945 on p53 andp21 detected by western blotting.

PLK-1 activation by CX-4945 induces cell cycle arrest. In particular, CX-4945 treatment increased the population of cells in the G2 phase compared to the untreated controls, indicating a G2 cell cycle arrest in both TFK-1 and SSP-25 (Figure 4). In addition, the cell population in the sub-G1 phase was increased by CX-4945 exposure, indicating an apoptotic response (14). These results revealed that the inhibition of CK2α by CX-4945 triggers cell cycle arrest and apoptosis in CCA cell lines (5). We further found that PLK1 is involved in the transition from G2 to M phase (15). The cross-talk between PLK1 and p53 for maintaining their homeostasis is well-described (16-18). The phospho-form of PLK1 (active form) was up-regulated by the treatment with CX-4945 (Figure 5A). The physiological correlation between PLK1 and p53 was also increased by exposure to CX-4945 in both the TFK-1 and SSP-25 lines (Figure 5B), and the level of p53 ubiquitination was higher (Figure 5C). These results suggest the possibility that the active form of PLK1 phosphorylates p53 leading to its ubiquitination (16). Taken together, our current data indicate that the activation of PLK1 by CX-4945 induces cell cycle arrest through p53 degradation and p21 modulation.

Figure 4.
Figure 4.

CX-4945 induces a G2 phase cell cycle arrest in cholangiocarcinoma cells. CCA cells were treated with CX-4945 (15 μM) for 48 and 72 h. The cells were then stained with Fx-Cycle PI/RNase staining solution and the populations of cells in each cell cycle phase were analyzed by flow cytometry.

Figure 5.
Figure 5.

CX-4945 regulates PLK1 and the ubiquitination of p53. (A) The CCA cells were treated with CX-4945 5 (15 μM) for 48 h and PLK1 phosphorylation was analyzed using western blot. (B, C) The CCA cells were treated with CX-4945 5 (15 μM) for 48 h and the effects of this inhibitor on p53 and on PLK1 phosphorylation, and the correlation between p53 and PLK1, were examined.

Discussion

Our current study demonstrated that the inhibition of CK2 by CX-4945 provokes cell cycle arrest at the G2 phase and an apoptotic response in CCA cell lines. Mechanistically, the exposure of these cells to CX-4945 altered the activity of PLK1 and led to the cell cycle arrest through the degradation of p53 and suppression of p21. In addition, cytosolic p53 was found to dissociate Bax from Bcl-xL as a consequence of a p53/ Bcl-xL complex formation. These free Bax proteins then triggered apoptosis. Therefore, our findings suggest that the inhibition of CK2 by CX-4945 is a potentially viable therapeutic strategy for CCA. Moreover, our data indicate that PLK1 may be a useful predictive marker for such CK2 targeted therapies.

CK2 is a serine/threonine kinase involved in the regulation of the cell cycle, DNA repair and other cellular processes, and alterations to its activity and its substrates have been associated with tumorigenesis (5, 6). CK2 over-expression has been observed in multiple types of cancers, including multiple myeloma, breast cancer, and lymphoma, and is associated with a poor prognosis (4, 7, 19). Recently, the CK2 inhibitor, silmitasertib (CX-4945) has entered clinical trials for locally advanced or metastatic CCA (NCT02128282) and has shown promising anti-tumor effects in combination with gemcitabine/ cisplatin (20). In addition, Di Maira et al. have reported that the inhibition of CK activity suppresses the malignant phenotype of CCA cells and increases their susceptibility to conventional chemotherapy (4, 21). However, the role of CK2 in the biology of CCA remains unclear.

We observed in our present analyses that the CK2 inhibitor CX-4945 induces a G2 phase cell cycle arrest in CCA cells by altering the activity of PLK1 (Figure 5A). This appears to be the most critical event among the consecutive intracellular changes induced by CX-4945 that triggered an apoptotic response in the tested CCA cell lines. PLK1 is a serine/threonine kinase that plays an important role in the G2/M transition of the cell cycle, the DNA damage response and DNA repair (9, 15). In general, the expression of PLK1 is low in normal tissues whereas active proliferating tissues show high levels of this kinase (17). The over-expression of PLK1 has been demonstrated in various tumor types such as nonsmall cell lung cancer (NSCLC), ovarian and breast cancers, and melanoma (22, 23). In addition, the over-expression of PLK1 has been correlated with a poor prognosis in NSCLC and colon cancer (23, 24). Inhibitors targeting this kinase such as volasertib and GSK461364A have been clinically developed for the treatment of AML and advanced solid tumors (15, 25).

We here observed that the PLK1 activated by CX-4945 suppresses p21 and p53 (18, 26). This modulation of PLK1 increased its physiological interaction with and phosphorylation of p53, resulting in the ubiquitination and degradation of p53. At the same time, the p21 cell cycle regulator was also found to be inactivated by CX-4945 (Figure 3B). This alteration of PLK1 by CX-4945 ultimately caused a cell cycle arrest through these effects on p53 and p21 in the TFK-1 and SSP-25 CCA cell lines (27). Taken together, these results indicated that the regulation of PLK1 activity via CK2 inhibition by CX-4945 represents a potential new approach to the treatment of CCAs and that PLK1 may be a predictive marker for such therapies.

Our analyses revealed that under conditions of CK2 inhibition by CX-4945 p53 regulation by PLK1 interrupted the interaction between Bcl-xL and Bax (Figure 3A). The resulting free Bax triggered apoptosis. Under physiological conditions, a complex id formed between pro-survival members (e.g., Bcl-2 and Bcl-xL) and pro-apoptotic members of the Bcl-2 family of proteins (e.g., Bax and Bak) that suppress the activity of the pro-apoptotic members (11-13). Under stress conditions, p53 binds to the pro-survival members to liberate Bax which provokes an apoptotic response (11-13). A recent study has reported that once p53 binds to Bcl-2 or Bcl-xL, p53/p21 complex formation will proceed (11). We thus investigated the physical interaction between p53 and p21 and found it to be decreased by CX4945 exposure (data not shown). This result indicated that CX-4945 disrupts the physical interaction between p53, p21, and Bcl-xL, thereby initiating cell cycle arrest and apoptosis.

In summary, we demonstrated that CK2 inhibition by CX4945 alters the activity of PLK1, leading to cell cycle arrest and apoptosis in the CCA cell lines TFK-1 and SSP-25. Based on these findings, we strongly suggest that CK2 is a new therapeutic target for CCA and that PLK1 is a predictive marker for CK2 inhibition.

Acknowledgements

This study was funded in part by grants from the Bio and Medical Technology Development Program of the National Research Foundation (NRF) of Korea, funded by the Ministry of Science, Communications Technology, and Future Planning of the Korean government (NRF-2016M3A9E8941331, NRF-2017M3A9G5061671, and NRF-2019R1F1A1061436), and the Asan Institute for Life Sciences at the Asan Medical Center in Seoul, Korea (2020IP0091-1) and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &Welfare, Republic of Korea (grant number: HI20C1586).

Footnotes

  • Authors’ Contributions

    Conceived and designed the study: Lee DS, Lee S, Kim KP, Yoo C. Collected the data: Lee DS, Lee S, Kim KP, Yoo C. Contributed to data or analysis tools: Lee DS, Lee S, Kim C, Kim D, Kim KP, Yoo C. Performed the analysis: Lee DS, Lee S, Kim KP, Yoo C. Wrote the paper: Lee DS, Lee S, Kim KP, Yoo C.

  • Conflicts of Interest

    The Authors have no conflicts of interest in relation to this study.

  • Received March 30, 2022.
  • Revision received May 24, 2022.
  • Accepted May 25, 2022.

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The Casein Kinase 2 Inhibitor CX-4945 Promotes Cholangiocarcinoma Cell Death Through PLK1
DA SOL LEE, SEONMIN LEE, CHORONG KIM, DANBEE KIM, KYU-PYO KIM, CHANGHOON YOO
Anticancer Research Jul 2022, 42 (7) 3435-3443; DOI: 10.21873/anticanres.15830
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