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Biol Open
2024 May 15;135:. doi: 10.1242/bio.060269.
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Na,K-ATPase activity promotes macropinocytosis in colon cancer via Wnt signaling.
Tejeda-Muñoz N
,
Azbazdar Y
,
Sosa EA
,
Monka J
,
Wei PS
,
Binder G
,
Mei KC
,
Kurmangaliyev YZ
,
De Robertis EM
.
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Recent research has shown that membrane trafficking plays an important role in canonical Wnt signaling through sequestration of the β-catenin destruction complex inside multivesicular bodies (MVBs) and lysosomes. In this study, we introduce Ouabain, an inhibitor of the Na,K-ATPase pump that establishes electric potentials across membranes, as a potent inhibitor of Wnt signaling. We find that Na,K-ATPase levels are elevated in advanced colon carcinoma, that this enzyme is elevated in cancer cells with constitutively activated Wnt pathway and is activated by GSK3 inhibitors that increase macropinocytosis. Ouabain blocks macropinocytosis, which is an essential step in Wnt signaling, probably explaining the strong effects of Ouabain on this pathway. In Xenopus embryos, brief Ouabain treatment at the 32-cell stage, critical for the earliest Wnt signal in development-inhibited brains, could be reversed by treatment with Lithium chloride, a Wnt mimic. Inhibiting membrane trafficking may provide a way of targeting Wnt-driven cancers.
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38713004
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P20CA016042 NIH HHS , UCLA BD-55 University of California, Los Angeles Jonsson Comprehensive Cancer Center, the Norman Sprague Endowment for Molecular Oncology, 910252-69 SUNY Binghamton faculty startup fund, RF1182424 SUNY Binghamton TAE Seed Grant, Oklahoma University, Stephenson Cancer Center, OUHSC: The University of Oklahoma Health Sciences Center, P30 CA016042 NCI NIH HHS , T32 GM149364 NIGMS NIH HHS , F31 MH131380 NIMH NIH HHS
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