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Cisplatin-Induced Apoptosis Involves Membrane Fluidification via Inhibition of NHE1 in Human Colon Cancer Cells

¹ Institut National de la Sante et de la Recherche Medicale, Unité Mixte de Recherche 620, Institut Fédératif de Recherche 140 Génétique Fonctionnelle Agronomie et Santé, and ² Unité Propre de Recherche de l'Enseignement Supérieur Equipe d'Accueil 3891, Univ Rennes 1, Rennes, France; ³ Institute of Toxicology, Mainz, Germany; ⁴ Laboratory of Cellular and Molecular Physiology, University of Nice-Sophia Antipolis, Nice, France; and ⁵ Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany

Requests for reprints: Marie-Thérèse Dimanche-Boitrel, Institut National de la Sante et de la Recherche Medicale UMR620, Faculté de Pharmacie, 2 Av du Pr Léon Bernard, 35043 Rennes, France. Phone: 33-0-2-23-23-48-37; Fax: 33-0-2-23-23-47-94; E-mail: marie-therese.boitrel{at}rennes.inserm.fr.

We have previously shown that cisplatin triggers an early acid sphingomyelinase (aSMase)-dependent ceramide generation concomitantly with an increase in membrane fluidity and induces apoptosis in HT29 cells. The present study further explores the role and origin of membrane fluidification in cisplatin-induced apoptosis. The rapid increase in membrane fluidity following cisplatin treatment was inhibited by membrane-stabilizing agents such as cholesterol or monosialoganglioside-1. In HT29 cells, these compounds prevented the early aggregation of Fas death receptor and of membrane lipid rafts on cell surface and significantly inhibited cisplatin-induced apoptosis without altering drug intracellular uptake or cisplatin DNA adducts formation. Early after cisplatin treatment, Na⁺/H⁺ membrane exchanger-1 (NHE1) was inhibited leading to intracellular acidification, aSMase was activated, and ceramide was detected at the cell membrane. Treatment of HT29 cells with Staphylococcus aureus sphingomyelinase increased membrane fluidity. Moreover, pretreatment with cariporide, a specific inhibitor of NHE1, inhibited cisplatin-induced intracellular acidification, aSMase activation, ceramide membrane generation, membrane fluidification, and apoptosis. Finally, NHE1-expressing PS120 cells were more sensitive to cisplatin than NHE1-deficient PS120 cells. Altogether, these findings suggest that the apoptotic pathway triggered by cisplatin involves a very early NHE1-dependent intracellular acidification leading to aSMase activation and increase in membrane fluidity. These events are independent of cisplatin-induced DNA adducts formation. The membrane exchanger NHE1 may be another potential target of cisplatin, increasing cell sensitivity to this compound. [Cancer Res 2007;67(16):7865–74]

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