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Open AccessArticle

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

1
Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Bangkok 10210, Thailand
2
Department of Biochemistry, Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand
3
Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand
4
Laboratory of Pharmacology, Chulabhorn Research Institute, Bangkok 10210, Thailand
5
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK
6
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
7
Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK
*
Authors to whom correspondence should be addressed.
Joint senior authors.
Cancers 2018, 10(9), 283; https://doi.org/10.3390/cancers10090283
Received: 2 August 2018 / Revised: 20 August 2018 / Accepted: 20 August 2018 / Published: 23 August 2018
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. View Full-Text
Keywords: protein kinase CK2; CX-4945; cholangiocarcinoma; non-canonical cell death; methuosis protein kinase CK2; CX-4945; cholangiocarcinoma; non-canonical cell death; methuosis
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MDPI and ACS Style

Lertsuwan, J.; Lertsuwan, K.; Sawasdichai, A.; Tasnawijitwong, N.; Lee, K.Y.; Kitchen, P.; Afford, S.; Gaston, K.; Jayaraman, P.-S.; Satayavivad, J. CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism. Cancers 2018, 10, 283. https://doi.org/10.3390/cancers10090283

AMA Style

Lertsuwan J, Lertsuwan K, Sawasdichai A, Tasnawijitwong N, Lee KY, Kitchen P, Afford S, Gaston K, Jayaraman P-S, Satayavivad J. CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism. Cancers. 2018; 10(9):283. https://doi.org/10.3390/cancers10090283

Chicago/Turabian Style

Lertsuwan, Jomnarong; Lertsuwan, Kornkamon; Sawasdichai, Anyaporn; Tasnawijitwong, Nathapol; Lee, Ka Y.; Kitchen, Philip; Afford, Simon; Gaston, Kevin; Jayaraman, Padma-Sheela; Satayavivad, Jutamaad. 2018. "CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism" Cancers 10, no. 9: 283. https://doi.org/10.3390/cancers10090283

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