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Plasma Membrane Electron Transport: A New Target for Cancer Drug Development

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The view that mitochondrial electron transport is the only site of aerobic respiration and the primary bioenergetic pathway in mammalian cells is well established in the literature. Although this paradigm is widely accepted for most tissues, the situation is less clear for proliferating cells. Increasing evidence indicates that glycolytic ATP production contributes substantially to fulfilling the energy requirements of rapidly dividing somatic cells, many tumour cells, and self-renewing stem cells in hypoxic environments. Glycolytic cells have been shown to consume oxygen at the cell surface via plasma membrane electron transport (PMET), a process that oxidises intracellular NADH, supports glycolytic ATP production and may contribute to aerobic energy production. PMET, as determined by reduction of a cell-impermeable tetrazolium dye, is highly active in rapidly-dividing tumour cell lines, where it ameliorates intracellular reductive stress, originating from the mitochondrial TCA cycle. Thus, mitochondrial NADH production is linked to dye reduction outside the cell via the malate-aspartate shuttle. PMET activity increases several-fold under hypoxic conditions, consistent with the view that oxygen competes for electrons from this PMET system. In addition, ° cells that lack mitochondrial electron transport are characterised by elevated PMET presumably to recycle NADH, a role traditionally assumed by lactate dehydrogenase. PMET presents an excellent target for developing novel anticancer drugs that exploit its unique plasma membrane localisation. We propose that PMET is a ubiquitous, high-capacity acute NADH redox-regulatory system responsible for maintaining the mitochondrial NADH/NAD+ ratio. Blocking this pathway compromises the viability of rapidly proliferating cells that rely on PMET.

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Keywords: Plasma membrane electron transport; WST-1; anti-cancer drugs; glycolytic metabolism; mitochondria; reductive stress

Document Type: Research Article

Affiliations: Malaghan Institute of Medical Research, PO Box 7060, Wellington, New Zealand.

Publication date: December 1, 2006

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  • Current Molecular Medicine is an interdisciplinary journal focused on providing the readership with current and comprehensive reviews on fundamental molecular mechanisms of disease pathogenesis, the development of molecular-diagnosis and/or novel approaches to rational treatment. The reviews should be of significant interest to basic researchers and clinical investigators in molecular medicine. Periodically the journal will invite guest editors to devote an issue on a basic research area that shows promise to advance our understanding of the molecular mechanism(s) of a disease or has potential for clinical applications.
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