NAD+/NADH and/or CoQ/CoQH2 ratios from plasma membrane electron transport may determine ceramide and sphingosine-1-phosphate levels accompanying G1 arrest and apoptosis.
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.
De Luca
Thomas
T
Department of Foods and Nutrition, Purdue University, West Lafayette, IN 47907, USA.
Morré
Dorothy M
DM
Zhao
Haiyun
H
Morré
D James
DJ
D019883:Alkyl and Aryl Transferases / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects*; D002462:Cell Membrane / Q000378:metabolism*; D002518:Ceramides / Q000378:metabolism*; D004579:Electron Transport / Q000502:physiology*; D016193:G1 Phase / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D008246:Lysophospholipids / Q000378:metabolism*; D009243:NAD / Q000502:physiology*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014451:Ubiquinone / Q000502:physiology*; D000099157:Sphingosine Kinase
D019883:Alkyl and Aryl Transferases; D002518:Ceramides; D007529:Isoflavones; D008246:Lysophospholipids; D009243:NAD; D009247:NADH, NADPH Oxidoreductases; D017853:Phosphotransferases (Alcohol Group Acceptor); D013108:Sphingomyelin Phosphodiesterase; D013110:Sphingosine; D014451:Ubiquinone; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C471183:phenoxodiol; C431909:tumor-associated NADH oxidase; C021386:4-hydroxybenzoate polyprenyltransferase