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Na,K-ATPase activity promotes macropinocytosis in colon cancer via Wnt signaling

Nydia Tejeda-Muñoz1,2,3, Yagmur Azbazdar1, Eric A Sosa4

  • 1Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles 90095-1662, USA.

Biology Open
|May 7, 2024
PubMed

Insights

Ouabain, a Na,K-ATPase pump inhibitor, effectively blocks Wnt signaling by inhibiting macropinocytosis. This finding suggests targeting membrane trafficking could be a novel strategy for treating Wnt-driven cancers.

Area of Science:

  • Cell Biology
  • Oncology
  • Biochemistry

Background:

  • Membrane trafficking is crucial for Wnt signaling, involving β-catenin destruction complex sequestration in multivesicular bodies (MVBs) and lysosomes.
  • Elevated Na,K-ATPase levels are observed in advanced colon carcinoma and cancer cells with activated Wnt pathways.

Purpose of the Study:

  • To investigate Ouabain, a Na,K-ATPase inhibitor, as a potential modulator of Wnt signaling.
  • To explore the role of Na,K-ATPase and macropinocytosis in Wnt pathway activation and cancer.

Main Methods:

  • Utilized Ouabain to inhibit Na,K-ATPase pump activity.
  • Assessed Na,K-ATPase levels in colon carcinoma and Wnt-activated cancer cells.
  • Investigated the effect of Ouabain on macropinocytosis in Wnt signaling.
  • Examined Ouabain's impact on Wnt signaling in Xenopus embryos.

Main Results:

  • Ouabain potently inhibits Wnt signaling, likely by blocking macropinocytosis, a key Wnt signaling step.
  • Na,K-ATPase is elevated in advanced colon carcinoma and Wnt-activated cancer cells.
  • GSK3 inhibitors activate Na,K-ATPase and increase macropinocytosis.
  • Ouabain treatment in Xenopus embryos inhibited brain development, which was reversible with lithium chloride.

Conclusions:

  • Na,K-ATPase inhibition by Ouabain offers a novel approach to target Wnt signaling.
  • Inhibiting membrane trafficking, specifically macropinocytosis, presents a potential therapeutic strategy for Wnt-driven cancers.
Keywords:
Xenopus laevisColorectal carcinomaK-ATPaseMacropinocytosisMultivesicular bodiesNaOuabainWnt signaling

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