NAD^{+}/NADH and/or CoQ/CoQH_{2} ratios from plasma membrane electron transport may determine ceramide and sphingosine-1-phosphate levels accompanying G_{1} arrest and apoptosis

Issue title: The Fourth Conference of the International CoQ10 Association

Article type: Research Article

Authors: De Luca, Thomas | Morré, Dorothy M. | Zhao, Haiyun | Morré, D. James

Affiliations: Department of Foods and Nutrition, Purdue University, West Lafayette, IN 47907, USA | Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA

Note: [] Address for correspondence: Dr. D.J. Morré, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 201 S. University Street, West Lafayette, IN 47907-2064, USA. Tel.: +1 765 494 1388; Fax: +1 765 494 4007; E-mail: [email protected]

Abstract: To elucidate possible biochemical links between growth arrest from antiproliferative chemotherapeutic agents and apoptosis, our work has focused on agents (EGCg, capsaicin, cis platinum, adriamycin, anti-tumor sulfonylureas, phenoxodiol) that target tNOX. tNOX is a cancer-specific cell surface NADH oxidase (ECTO-NOX protein), that functions in cancer cells as the terminal oxidase for plasma membrane electron transport. When tNOX is active, coenzyme Q_{10} (ubiquinone) of the plasma membrane is oxidized and NADH is oxidized at the cytosolic surface of the plasma membrane. However, when tNOX is inhibited and plasma membrane electron transport is diminished, both reduced coenzyme Q_{10} (ubiquinol) and NADH would be expected to accumulate. To relate inhibition of plasma membrane redox to increased ceramide levels and arrest of cell proliferation in G_{1} and apoptosis, we show that neutral sphingomyelinase, a major contributor to plasma membrane ceramide, is inhibited by reduced glutathione and ubiquinone. Ubiquinol is without effect or stimulates. In contrast, sphingosine kinase, which generates anti-apoptotic sphingosine-1-phosphate, is stimulated by ubiquinone but inhibited by ubiquinol and NADH. Thus, the quinone and pyridine nucleotide products of plasma membrane redox, ubiquinone and ubiquinol, as well as NAD^{+} and NADH, may directly modulate in a reciprocal manner two key plasma membrane enzymes, sphingomyelinase and sphingosine kinase, potentially leading to G_{1} arrest (increase in ceramide) and apoptosis (loss of sphingosine-1-phosphate). As such, the findings provide potential links between coenzyme Q_{10}-mediated plasma membrane electron transport and the anticancer action of several clinically-relevant anticancer agents.

Keywords: Apoptosis, ECTO-NOX, NADH oxidase, tNOX, cancer, capsaicin, ceramide, coenzyme Q, (-)-epigallocatechin-3-gallate (EGCg), plasma membrane electron transport, sphingomyelinase, sphingosine-1-phosphate, sphingosine kinase

Journal: BioFactors, vol. 25, no. 1-4, pp. 43-60, 2005