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Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells

Desheng Lu1, Michael Y Choi, Jian Yu

  • 1University of California at San Diego Moores Cancer Center, La Jolla, CA 92093-0820, USA. delu@ucsd.edu

Proceedings of the National Academy of Sciences of the United States of America
|July 27, 2011
PubMed

Insights

Salinomycin, a potassium ionophore, inhibits Wnt signaling by blocking LRP6 phosphorylation, offering a new strategy against Wnt-dependent cancers like leukemia. This antibiotic targets cancer stem cells selectively.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Salinomycin selectively inhibits breast cancer stem cells, but its mechanism is unclear.
  • Aberrant Wnt/β-catenin signaling drives stem cell development and cancer.
  • Understanding salinomycin's action is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To elucidate the biochemical basis of salinomycin's anticancer effects.
  • To investigate salinomycin's impact on the Wnt/β-catenin signaling pathway.
  • To determine if salinomycin's inhibition of Wnt signaling is selective for cancer cells.

Main Methods:

  • Investigated salinomycin's effect on Wnt signaling in Wnt-transfected HEK293 cells.
  • Examined LRP6 phosphorylation and degradation upon salinomycin treatment.
  • Assessed salinomycin's impact on Wnt target gene expression and survival in chronic lymphocytic leukemia cells.

Main Results:

  • Salinomycin potently inhibited the Wnt signaling cascade by blocking LRP6 phosphorylation and inducing its degradation.
  • Similar effects were observed with nigericin, another potassium ionophore.
  • Salinomycin down-regulated Wnt target genes (LEF1, cyclin D1, fibronectin), reduced LRP6 levels, and limited survival in leukemia cells.
  • Normal lymphocytes showed resistance to salinomycin toxicity.

Conclusions:

  • Ionic changes induced by salinomycin inhibit proximal Wnt signaling via LRP6 phosphorylation interference.
  • This mechanism impairs the survival of Wnt signaling-dependent cancer cells.
  • Salinomycin represents a potential therapeutic agent for Wnt-driven cancers, including leukemia.

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