Displacement of Native FXYD Protein From Na+/K+-ATPase With Novel FXYD Peptide Derivatives: Effects on Doxorubicin Cytotoxicity

• DOI: 10.3389/fonc.2022.859216
• Publication Date: 2022-03-17T08:09:14Z
• Authors: Chia-Chi Liu; Yeon Jae Kim; Rachel Teh; Alvaro Garcia; Elisha J. Hamilton; Flemming Cornelius; Robert C. Baxter; Helge H. Rasmussen
• Keywords: 0301 basic medicine; 570; peptide therapy; membrane transport; pancreatic cancer; 610; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; 3. Good health; 03 medical and health sciences; breast cancer; Oncology; XXXXXX - Unknown; dysadherin; oxidative stress; RC254-282

The seven mammalian FXYD proteins associate closely with α/β heterodimers of Na+/K+-ATPase. Most them protect the β1 subunit against glutathionylation, an oxidative modification that destabilizes heterodimer and inhibits Na+/K+-ATPase activity. A specific cysteine (Cys) residue is critical for such protection. One proteins, FXYD3, confers treatment resistance when overexpressed in cancer cells. We developed two FXYD3 peptide derivatives. FXYD3-pep CKCK retained Cys can undergo glutathionylation protecting glutathionylation. SKSK had all residues mutated to Serine (Ser). chemotherapeutic doxorubicin induces stress, suppression siRNA pancreatic- breast cells strongly express increased doxorubicin-induced cytotoxicity. Exposing decreased co-immunoprecipitation α1 subunit. reproduced increase cytotoxicity seen after transfection while boosted native protein's protection doxorubicin. Neither affected doxorubicin's on no or low expression. Fluorescently labeled was detected a perinuclear distribution overexpressing plasmalemmal turnover could not be implicated sensitivity caused. derivatives allow rapid elimination amplification protein function. Here, their effects implicate countering augmentation siRNA-induced downregulation FXYD3.