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- W4246962110 abstract "Abstract Background FXYD proteins associate closely with- and protect plasmalemmal Na + /K + -ATPase against oxidative inhibition. One of them, FXYD3, is often overexpressed in cancers, including those of breast and pancreas. Down-regulation of overexpression in MCF-7 breast cancer cells with siRNA augments doxorubicin-induced cytotoxicity. Because down-regulation with siRNA is not readily translated therapeutically, we developed a peptide as an alternative for suppression of FXYD3. Methods A shortened peptide derivative of the wild-type (WT) FXYD3 protein, FXYD3-pep has the four cysteine residues in the WT protein replaced by serine, which eliminates the WT protein’s protection against oxidative Na + /K + -ATPase inhibition. We exposed human cancer cells to FXYD3-pep and measured cytotoxicity and caspase 3/7 activity with co-exposure to doxorubicin. We also measured effects of the peptide on expression glutathione-S-transferase π (GST-π), implicated in treatment resistance, and on expression of tumor suppressor p53. Selected experiments were performed with parallel FXYD3 suppression with siRNA or FXYD3-pep. Results Exposure of cells to FXYD3-pep displaced WT FXYD3 from Na + /K + -ATPase. Exposure of MCF-7 breast or pancreatic BxPC-3 cancer cells that highly express FXYD3 to the peptide had little effect alone but combined with doxorubicin it significantly (P < 0.05) increased cytotoxicity. A peptide not mutated to eliminate FXYD3’s protective effect of Na + /K + -ATPase had no effect. FXYD3-pep did not augment doxorubicin’s cytotoxicity against MDA-MB-468 breast and Panc-1 pancreatic cancer cells that have low- or no FXYD3 expression. Cellular FXYD3 expressions was reflected by expression of the α1 Na + /K + -ATPase subunits but not by plasmalemmal Na + /K + -ATPase function. Signals from fluorescently labeled FXYD3-pep were detected in a perinuclear distribution in BxPC-3 cells as reported for overexpressed FXYD3, α- and β Na + /K + -ATPase subunits in cancer. Exposure to FXYD3-pep or to FXYD3 siRNA almost eliminated expression of GST-π. FXYD3-pep alone had no effect on p53 levels but significantly augmented a doxorubicin-induced increase, and, while the peptide alone had no effect on caspase 3/7 activity, it significantly augmented a doxorubicin-induced increase. Conclusions Overexpressed FXYD3 has intracellular roles beyond its accepted modulation of plasmalemmal Na + /K + -ATPase. These roles can be countered with a membrane-permeable peptide derivative of FXYD3 that suppresses GST-π and enhances chemosensitivity of cancer cells overexpressing FXYD3." @default.
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- W4246962110 date "2020-07-14" @default.
- W4246962110 modified "2023-09-28" @default.
- W4246962110 title "Na+/K+-ATPase-associated FXYD3 Protein As An Intracellular Therapeutic Target in Cancer" @default.
- W4246962110 doi "https://doi.org/10.21203/rs.3.rs-41003/v1" @default.
- W4246962110 hasPublicationYear "2020" @default.
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