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

Research output: Contribution to journalArticle

Authors

  • Jomnarong Lertsuwan
  • Kornkamon Lertsuwan
  • Anyaporn Sawasdichai
  • Nathapol Tasnawijitwong
  • Ka Ying Lee
  • Kevin Gaston
  • Jutamaad Satayavivad

External organisations

  • Department of Biochemistry, Faculty of Science, Mahidol University
  • Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute
  • Laboratory of Pharmacology, Chulabhorn Research Institute
  • School of Medicine, University of Nottingham

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.

Details

Original languageEnglish
Article number283
Number of pages22
JournalCancers
Volume10
Issue number9
Publication statusPublished - 23 Aug 2018

Keywords

  • protein kinase CK2, CX-4945, cholangiocarcinoma, non-canonical cell death, methuosis