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.

Abstract

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.

Citation

Sherman, H. G., Jovanovic, C., Abuawad, A., Kim, D.-H., Collins, H., Dixon, J. E., Cavanagh, R., Markus, R., Stolnik, S., & Rawson, F. J. (2019). Mechanistic insight into heterogeneity of trans-plasma membrane electron transport in cancer cell types. BBA - Bioenergetics, 1860(8), 628-639. https://doi.org/10.1016/j.bbabio.2019.06.012

• 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: Biochimica et Biophysica Acta (BBA) - Bioenergetics
• Print ISSN: 0005-2728
• Electronic ISSN: 1879-2650
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 1860
• Issue: 8
• Pages: 628-639
• DOI: https://doi.org/10.1016/j.bbabio.2019.06.012
• Keywords: Trans-plasma membrane electron transport (tPMET); Ascorbic acid; Ascorbate shuttle; Electrochemistry; Lung epithelium; Cancer; GLUT transport; Anion channels; Ferri-ireduction
• Public URL: https://nottingham-repository.worktribe.com/output/2263305
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0005272818306637?via%3Dihub
• Contract Date: Jul 3, 2019