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

Cancers
Jomnarong LertsuwanJutamaad Satayavivad

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 ce...Continue Reading

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Citations

Dec 11, 2019·Cell Biology and Toxicology·J Grace Nirmala, Manu Lopus
Feb 6, 2020·International Journal of Molecular Sciences·Kornkamon LertsuwanJomnarong Lertsuwan
Apr 24, 2021·Journal of Applied Toxicology : JAT·Xiuge GaoShanxiang Jiang
May 18, 2021·Signal Transduction and Targeted Therapy·Christian BorgoMaria Ruzzene
Jul 13, 2021·Frontiers in Cell and Developmental Biology·Markus RitterHubert H Kerschbaum
Oct 15, 2020·Cellular Oncology (Dordrecht)·Claudio D'AmoreMauro Salvi
Aug 4, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Claudio D'AmoreMauro Salvi

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Methods Mentioned

BETA
xenograft
gene knockdown

Clinical Trials Mentioned

NCT02128282

Software Mentioned

Adobe Photoshop
GraphPad
JMP
Prism Graphpad

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