title: Intracellular NAD(H) levels control motility and invasion of glioma cells.
abstract: Oncogenic transformation involves reprogramming of cell metabolism, whereby steady-state levels of intracellular NAD(+) and NADH can undergo dramatic changes while ATP concentration is generally well maintained. Altered expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD(+)-salvage, accompanies the changes in NAD(H) during tumorigenesis. Here, we show by genetic and pharmacological inhibition of NAMPT in glioma cells that fluctuation in intracellular [NAD(H)] differentially affects cell growth and morphodynamics, with motility/invasion capacity showing the highest sensitivity to [NAD(H)] decrease. Extracellular supplementation of NAD(+) or re-expression of NAMPT abolished the effects. The effects of NAD(H) decrease on cell motility appeared parallel coupled with diminished pyruvate-lactate conversion by lactate dehydrogenase (LDH) and with changes in intracellular and extracellular pH. The addition of lactic acid rescued and knockdown of LDH-A replicated the effects of [NAD(H)] on motility. Combined, our observations demonstrate that [NAD(H)] is an important metabolic component of cancer cell motility. Nutrient or drug-mediated modulation of NAD(H) levels may therefore represent a new option for blocking the invasive behavior of tumors.
authors.affiliation: Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. r.vanhorssen@ncmls.ru.nl
authors.forename: Remco
authors.initials: R
authors.lastname: van Horssen
authors.forename: Marieke
authors.initials: M
authors.lastname: Willemse
authors.forename: Anna
authors.initials: A
authors.lastname: Haeger
authors.forename: Francesca
authors.initials: F
authors.lastname: Attanasio
authors.forename: Tuba
authors.initials: T
authors.lastname: Güneri
authors.forename: Albrecht
authors.initials: A
authors.lastname: Schwab
authors.forename: Christian M
authors.initials: CM
authors.lastname: Stock
authors.forename: Roberto
authors.initials: R
authors.lastname: Buccione
authors.forename: Jack A M
authors.initials: JA
authors.lastname: Fransen
authors.forename: Bé
authors.initials: B
authors.lastname: Wieringa
mesh_terms: D015152:Blotting, Northern; D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005910:Glioma / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000494:pharmacology; D009243:NAD / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D059008:Time-Lapse Imaging; D014407:Tumor Cells, Cultured
chemical_list: D009243:NAD; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase; D054409:Nicotinamide Phosphoribosyltransferase