This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Huc, L. Articles by Lagadic-Gossmann, D. Search for Related Content PubMed PubMed Citation Articles by Huc, L. Articles by Lagadic-Gossmann, D.

c-Jun NH₂-Terminal Kinase–Related Na⁺/H⁺ Exchanger Isoform 1 Activation Controls Hexokinase II Expression in Benzo(a)Pyrene-Induced Apoptosis

¹ Institut National de la Santé et de la Recherche Médicale U620, Université Rennes 1, IFR 140, Rennes, France and ² Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo, Norway

Requests for reprints: Dominique Lagadic-Gossmann, Institut National de la Santé et de la Recherche Médicale U620, Faculté de Pharmacie, 2 Av du Pr Léon Bernard, 35043 Rennes, France. Phone: 33-2-23-23-48-37; Fax: 33-2-23-23-47-94; E-mail: dominique.lagadic{at}rennes.inserm.fr.

Regulation of the balance between survival, proliferation, and apoptosis on carcinogenic polycyclic aromatic hydrocarbon (PAH) exposure is still poorly understood and more particularly the role of physiologic variables, including intracellular pH (pH_i). Although the involvement of the ubiquitous pH_i regulator Na⁺/H⁺ exchanger isoform 1 (NHE1) in tumorigenesis is well documented, less is known about its role and regulation during apoptosis. Our previous works have shown the primordial role of NHE1 in carcinogenic PAH-induced apoptosis. This alkalinizing transporter was activated by an early CYP1-dependent H₂O₂ production, subsequently promoting mitochondrial dysfunction leading to apoptosis. The aim of this study was to further elucidate how NHE1 was activated by benzo(a)pyrene (BaP) and what the downstream events were in the context of apoptosis. Our results indicate that the mitogen-activated protein kinase kinase 4/c-Jun NH₂-terminal kinase (MKK4/JNK) pathway was a link between BaP-induced H₂O₂ production and NHE1 activation. This activation, in combination with BaP-induced phosphorylated p53, promoted mitochondrial superoxide anion production, supporting the existence of a common target for NHE1 and p53. Furthermore, we showed that the mitochondrial expression of glycolytic enzyme hexokinase II (HKII) was decreased following a combined action of NHE1 and p53 pathways, thereby enhancing the BaP-induced apoptosis. Taken together, our findings suggest that, on BaP exposure, MKK4/JNK targets NHE1 with consequences on HKII protein, which might thus be a key protein during carcinogenic PAH apoptosis. [Cancer Res 2007;67(4):1696–705]