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

Jomnarong Lertsuwan, Kornkamon Lertsuwan, Anyaporn Sawasdichai, Nathapol Tasnawijitwong, Ka Ying Lee, Philip Kitchen, Simon Afford, Kevin Gaston, Padma-Sheela Jayaraman, Jutamaad Satayavivad

Research output: Contribution to journalArticle

Abstract

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.
Original languageEnglish
Article number283
JournalCancers
Volume10
Issue number9
DOIs
Publication statusPublished - 23 Aug 2018

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Cholangiocarcinoma
Casein Kinase II
Cell Line
Vacuoles
Neoplasms
Extracellular Fluid
Metalloproteases
Protein Kinases
Small Interfering RNA
5-(3-chlorophenylamino)benzo(c)(2,6)naphthyridine-8-carboxylic acid
Catalytic Domain
Cell Death
Up-Regulation
Cell Proliferation
Incidence
Pharmaceutical Preparations

Bibliographical note

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Cite this

Lertsuwan, J., Lertsuwan, K., Sawasdichai, A., Tasnawijitwong, N., Lee, K. Y., Kitchen, P., ... Satayavivad, J. (2018). CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism. Cancers, 10(9), [283]. https://doi.org/10.3390/cancers10090283
Lertsuwan, Jomnarong ; Lertsuwan, Kornkamon ; Sawasdichai, Anyaporn ; Tasnawijitwong, Nathapol ; Lee, Ka Ying ; Kitchen, Philip ; Afford, Simon ; Gaston, Kevin ; Jayaraman, Padma-Sheela ; Satayavivad, Jutamaad. / CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism. In: Cancers. 2018 ; Vol. 10, No. 9.
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Lertsuwan, J, Lertsuwan, K, Sawasdichai, A, Tasnawijitwong, N, Lee, KY, Kitchen, P, Afford, S, Gaston, K, Jayaraman, P-S & Satayavivad, J 2018, 'CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism', Cancers, vol. 10, no. 9, 283. https://doi.org/10.3390/cancers10090283

CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism. / Lertsuwan, Jomnarong; Lertsuwan, Kornkamon; Sawasdichai, Anyaporn; Tasnawijitwong, Nathapol; Lee, Ka Ying; Kitchen, Philip; Afford, Simon; Gaston, Kevin; Jayaraman, Padma-Sheela; Satayavivad, Jutamaad.

In: Cancers, Vol. 10, No. 9, 283, 23.08.2018.

Research output: Contribution to journalArticle

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T1 - CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism

AU - Lertsuwan, Jomnarong

AU - Lertsuwan, Kornkamon

AU - Sawasdichai, Anyaporn

AU - Tasnawijitwong, Nathapol

AU - Lee, Ka Ying

AU - Kitchen, Philip

AU - Afford, Simon

AU - Gaston, Kevin

AU - Jayaraman, Padma-Sheela

AU - Satayavivad, Jutamaad

N1 - This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

PY - 2018/8/23

Y1 - 2018/8/23

N2 - 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.

AB - 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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Lertsuwan J, Lertsuwan K, Sawasdichai A, Tasnawijitwong N, Lee KY, Kitchen P et al. CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism. Cancers. 2018 Aug 23;10(9). 283. https://doi.org/10.3390/cancers10090283