title: c-Jun NH2-terminal kinase-related Na+/H+ exchanger isoform 1 activation controls hexokinase II expression in benzo(a)pyrene-induced apoptosis.
abstract: 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 H(2)O(2) 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 NH(2)-terminal kinase (MKK4/JNK) pathway was a link between BaP-induced H(2)O(2) 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U620, Université Rennes 1, IFR 140, 2 Avenue du Pr. Léon Bernard, Rennes, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Huc
authors.forename: Xavier
authors.initials: X
authors.lastname: Tekpli
authors.forename: Jørn A
authors.initials: JA
authors.lastname: Holme
authors.forename: Mary
authors.initials: M
authors.lastname: Rissel
authors.forename: Anita
authors.initials: A
authors.lastname: Solhaug
authors.forename: Claire
authors.initials: C
authors.lastname: Gardyn
authors.forename: Gwénaelle
authors.initials: G
authors.lastname: Le Moigne
authors.forename: Morgane
authors.initials: M
authors.lastname: Gorria
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Dimanche-Boitrel
authors.forename: Dominique
authors.initials: D
authors.lastname: Lagadic-Gossmann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001564:Benzo(a)pyrene / Q000494:pharmacology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006593:Hexokinase / Q000096:biosynthesis*; D006861:Hydrogen Peroxide / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000096:biosynthesis / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; C452850:Slc9a1 protein, rat; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D016159:Tumor Suppressor Protein p53; D001564:Benzo(a)pyrene; D006861:Hydrogen Peroxide; D006593:Hexokinase; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4