Abstract
Cholangiocarcinoma (CCA) is a particularly aggressive hepatobiliary malignancy, for which the molecular mechanisms underlying the malignant phenotype are still poorly understood, and novel and effective therapeutic strategies are limited. The pro-survival protein kinase CK2 is frequently overexpressed in cancer and is receiving increasing interest as an anti-tumor drug target. Its precise role in CCA biology is still largely unknown. Here we show that expression of the CK2α and α’ catalytic subunits and of the β regulatory subunit is increased in human CCA samples. Increased expression of CK2 subunits was shown in CCA cell lines compared to non-transformed cholangiocytes. We used chemical inhibition of CK2 and genetic modification by CRISPR/Cas9 to explore the contribution of CK2 to the malignant phenotype of CCA cells. Disruption of CK2 activity results in cell death through apoptosis, reduced invasion and migration potential, and G0/G1 cell cycle arrest. Importantly, CCA cells with a reduced CK2 activity are more sensitive to chemotherapy. Altogether, our results demonstrate that CK2 significantly contributes to increased proliferative potential and augmented growth of CCA cells and indicate the rationale for its targeting as a promising pharmacologic strategy for cholangiocarcinoma.
Highlights
Cholangiocarcinoma (CCA) is a lethal form of cancer which accounts for approximately 10–25% of all hepatobiliary malignancies[1]
CK2 activity was reduced in a dose-dependent manner by CX4945 in HUCCT-1 cells (Fig. 2a), and the drop of CK2 kinase activity by CX4945 was confirmed by dephosphorylation of AktS129 (Fig. 2b)
CK2 inhibition induces apoptosis in CCA cells We investigated whether the reduction of CCA cell viability in response to CX4945 was due to induction of Because in other studies CX4945 was reported to induce methuosis[24,25], we checked whether this phenomenon occurred under our experimental conditions
Summary
Cholangiocarcinoma (CCA) is a lethal form of cancer which accounts for approximately 10–25% of all hepatobiliary malignancies[1]. CK2 phosphorylates hundreds of substrates and is involved in many cellular processes[6] While it is ubiquitously expressed, higher levels have been found in cancer cells as compared to healthy cells[7,8]. Several CK2 inhibitors with cytotoxic properties in tumor cells and anti-cancer effects in animal models have been developed[16,17]. The direct involvement of CK2 in CCA has been reported in a study showing that CX4945 has an anti-proliferative effect on CCA cells in vitro, and in mouse xenograft models[19]. A study in primary CCA cells demonstrated a pro-apoptotic effect of CX4945 in correlation with CK2 expression levels, and suggested the potential benefit of a combined CK2/TGF-β targeting[20]. We provide a novel insight into the molecular mechanisms by which CK2 contributes to the malignant phenotype of CCA, exploiting pharmacologic and genetic approaches
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
