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Mechanistic insight into heterogeneity of trans-plasma membrane electron transport in cancer cell types

Sherman, Harry G.; Jovanovic, Carolyn; Abuawad, Alaa; Kim, Dong-Hyun; Collins, Hilary; Dixon, James E.; Cavanagh, Robert; Markus, Robert; Stolnik, Snow; Rawson, Frankie J.

Mechanistic insight into heterogeneity of trans-plasma membrane electron transport in cancer cell types Thumbnail


Harry G. Sherman

Carolyn Jovanovic

Alaa Abuawad

James E. Dixon

Robert Markus

Snow Stolnik


Trans-plasma membrane electron transfer (tMPET) is a process by which reducing equivalents, either electrons or reductants like ascorbic acid, are exported to the extracellular environment by the cell. TPMET is involved in a number of physiological process and has been hypothesised to play a role in the redox regulation of cancer metabolism. Here, we use a new electrochemical assay to elucidate the ‘preference’ of cancer cells for different trans tPMET systems. This aids in proving a biochemical framework for the understanding of tPMET role, and for the development of novel tPMET-targeting therapeutics. We have delineated the mechanism of tPMET in 3 lung cancer cell models to show that the external electron transfer is orchestrated by ascorbate mediated shuttling via tPMET. In addition, the cells employ a different, non-shuttling-based mechanism based on direct electron transfer via Dcytb. Results from our investigations indicate that tPMETs are used differently, depending on the cell type. The data generated indicates that tPMETs may play a fundamental role in facilitation of energy reprogramming in malignant cells, whereby tPMETs are utilised to supply the necessary energy requirement when mitochondrial stress occurs. Our findings instruct a deeper understanding of tPMET systems, and show how different cancer cells may preferentially use distinguishable tPMET systems for cellular electron transfer processes.

Journal Article Type Article
Acceptance Date Jun 19, 2019
Online Publication Date Jun 20, 2019
Publication Date Aug 1, 2019
Deposit Date Jul 3, 2019
Publicly Available Date Jan 14, 2020
Journal BBA - Bioenergetics
Print ISSN 0005-2728
Electronic ISSN 1879-2650
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 1860
Issue 8
Pages 628-639
Keywords Trans-plasma membrane electron transport (tPMET); Ascorbic acid; Ascorbate shuttle; Electrochemistry; Lung epithelium; Cancer; GLUT transport; Anion channels; Ferri-ireduction
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