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Title: Therapeutic potential of aptamer-mediated targeting of the voltage-gated Na+ channel beta1 subunit in human breast cancer cells
Author: Patel, Faheemmuddeen
ISNI:       0000 0004 7964 6452
Awarding Body: University of York
Current Institution: University of York
Date of Award: 2018
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Voltage-gated sodium channels (VGSCs), classically responsible for action potential firing in excitable cells, also play an important role in non-excitable cells and in particular, cancer cells. VGSCs contain a pore-forming alpha subunit and one or more auxiliary beta subunits, which contain immunoglobulin (Ig) loops and function as cell adhesion molecules (CAMs). The VGSC  subunit, NaV1.5, and its auxiliary beta1 subunit have been shown to increase invasion of breast cancer cells and metastasis in a xenograft mouse model of breast cancer. In addition, beta1 expression is increased in breast cancer specimens relative to control samples. Thus, beta1 may serve as a valuable therapeutic target to inhibit metastasis. The hypothesis of this project was that the Ig domain of beta1 is critical for regulating its function as an auxiliary channel subunit and a cell adhesion molecule (CAM) in breast cancer cells such that aptamers targeting the Ig domain would abrogate its function. This project used various approaches to block the function of the Ig loop, including truncations, amino acid substitutions, antibodies and aptamers, and evaluated these perturbations in adhesion assays and whole cell patch clamp recordings of the INa. The data presented in this Thesis demonstrate: (1) the ability of the beta1 subunit to act as a CAM in breast cancer cells through homophilic interactions between the extracellularly located Ig loop of β1; (2) a mechanism by which beta1 may increase the Na+ current in breast cancer cells via regulation of expression of another alpha-subunit subtype, through cleavage of the intracellular domain; (3) the importance of the beta1 Ig loop to support its function as both a CAM and modulator of Na+ current; (4) the potential interplay between beta1 and L1CAM, another CAM whose expression is increased in breast cancer, in regulating adhesion and invasion; and (5) that aptamers raised using the cell-SELEX approach to target the Ig domain of beta1 can inhibit its adhesion-dependent activity. The data thus underscore the potential utility of inhibiting beta1 function in breast cancer cells using Ig domain-directed aptamers and highlight a potential mechanism through which increased expression of β1 and Na+ current may potentiate invasion and/or migration.
Supervisor: Brackenbury, William ; Maitland, Norman ; Bunka, David Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available