The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Ivan Scheblykin. Portrait.

Ivan Scheblykin

Professor

Ivan Scheblykin. Portrait.

The Molecular Basis for Inhibition of Stemlike Cancer Cells by Salinomycin

Author

  • Xiaoli Huang
  • Björn Borgström
  • John Stegmayr
  • Yasmin Abassi
  • Monika Kruszyk
  • Hakon Leffler
  • Lo Persson
  • Sebastian Albinsson
  • Ramin Massoumi
  • Ivan G. Scheblykin
  • Cecilia Hegardt
  • Stina Oredsson
  • Daniel Strand
Show all

Summary, in English

Tumors are phenotypically heterogeneous and include subpopulations of cancer cells with stemlike properties. The natural product salinomycin, a K+-selective ionophore, was recently found to exert selectivity against such cancer stem cells. This selective effect is thought to be due to inhibition of the Wnt signaling pathway, but the mechanistic basis remains unclear. Here, we develop a functionally competent fluorescent conjugate of salinomycin to investigate the molecular mechanism of this compound. By subcellular imaging, we demonstrate a rapid cellular uptake of the conjugate and accumulation in the endoplasmic reticulum (ER). This localization is connected to induction of Ca2+ release from the ER into the cytosol. Depletion of Ca2+ from the ER induces the unfolded protein response as shown by global mRNA analysis and Western blot analysis of proteins in the pathway. In particular, salinomycin-induced ER Ca2+ depletion up-regulates C/EBP homologous protein (CHOP), which inhibits Wnt signaling by down-regulating β-catenin. The increased cytosolic Ca2+ also activates protein kinase C, which has been shown to inhibit Wnt signaling. These results reveal that salinomycin acts in the ER membrane of breast cancer cells to cause enhanced Ca2+ release into the cytosol, presumably by mediating a counter-flux of K+ ions. The clarified mechanistic picture highlights the importance of ion fluxes in the ER as an entry to inducing phenotypic effects and should facilitate rational development of cancer treatments.

Department/s

  • Department of Biology
  • Centre for Analysis and Synthesis
  • Department of Laboratory Medicine
  • Division of Translational Cancer Research
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
  • Department of Experimental Medical Science
  • Chemical Physics
  • NanoLund: Centre for Nanoscience
  • Breastcancer-genetics

Publishing year

2018-06-27

Language

English

Pages

760-767

Publication/Series

ACS Central Science

Volume

4

Issue

6

Document type

Journal article

Publisher

The American Chemical Society (ACS)

Topic

  • Cell and Molecular Biology
  • Cancer and Oncology

Status

Published

ISBN/ISSN/Other

  • ISSN: 2374-7943