c-Jun NH2-Terminal Kinase–Related Na+/H+ Exchanger Isoform 1 Activation Controls Hexokinase II Expression in Benzo(a)Pyrene-Induced Apoptosis
Open Access
- 15 February 2007
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 67 (4), 1696-1705
- https://doi.org/10.1158/0008-5472.can-06-2327
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 (pHi). Although the involvement of the ubiquitous pHi 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]Keywords
Other Versions
This publication has 46 references indexed in Scilit:
- N-(4-Hydroxyphenyl)retinamide-induced apoptosis triggered by reactive oxygen species is mediated by activation of MAPKs in head and neck squamous carcinoma cellsOncogene, 2006
- Modulation of gene expression and DNA adduct formation in HepG2 cells by polycyclic aromatic hydrocarbons with different carcinogenic potenciesCarcinogenesis: Integrative Cancer Research, 2005
- Polycyclic aromatic hydrocarbons induce an inflammatory atherosclerotic plaque phenotype irrespective of their DNA binding propertiesThe FASEB Journal, 2005
- Mitochondrial Bound Hexokinase Activity as a Preventive Antioxidant DefenseJournal of Biological Chemistry, 2004
- Alterations of intracellular pH homeostasis in apoptosis: origins and rolesCell Death & Differentiation, 2004
- Differential effects of polycyclic aromatic hydrocarbons on transactivation of AP-1 and NF-?B in mouse epidermal cl41 cellsMolecular Carcinogenesis, 2004
- mtCLIC is up‐regulated and maintains a mitochondrial membrane potential in mtDNA‐depleted L929 cellsThe FASEB Journal, 2003
- MitochondriaCell, 2003
- The Changing Face of the Na+/H+ Exchanger, NHE1: Structure, Regulation, and Cellular ActionsAnnual Review of Pharmacology and Toxicology, 2002
- Involvement of Alpha-PAK-Interacting Exchange Factor in the PAK1–c-Jun NH2-Terminal Kinase 1 Activation and Apoptosis Induced by Benzo[a]pyreneMolecular and Cellular Biology, 2001