p-Nonylphenol induces endoplasmic reticulum stress-mediated apoptosis in neuronally differentiated PC12 cells.
Endocrine disrupting chemicals (EDCs) induce estrogenic phenotypes in sexual organs and cells by chronic stimulation through binding to estrogen receptors. Although cell death may be induced instead of phenotypic change by EDCs in germ cells, the mechanism of the effect of EDCs in neuronal cells is still obscure. Here we report that p-nonylphenol, one of the EDCs, induced apoptosis with up-regulation of glucose-regulated protein 78 (GRP78) expression and activation of caspase-12, which are involved in endoplasmic reticulum (ER) stress specific phenomena, in NGF-treated neuronally differentiated PC12 cells. Moreover, we observed that p-nonylphenol increased the intracellular Ca(2+) concentration and p-nonylphenol-induced apoptosis was prevented when BAPTA-AM, a membrane-permeable Ca(2+) chelator, was added. Intriguingly, we also discovered that decreased phosphorylation of ERK1/2 was induced by p-nonylphenol in the presence of NGF, whereas p-nonylphenol alone did not induce phosphorylation of ERK1/2. These lines of evidence suggest that p-nonylphenol can induce ER stress-mediated apoptosis via increased intracellular Ca(2+) concentration, and can reduce ERK1/2 phosphorylation to attenuate the cell survival effect of NGF, in neuronally differentiated PC12 cells.
Kusunoki
Takashi
T
Laboratory of Neurobiology, Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering and High Technology Research Center (HRC), Kansai University, 3-3-35 Yamate-cho, Suita, Osaka 564-8680, Japan.
Shimoke
Koji
K
Komatsubara
Satoko
S
Kishi
Soichiro
S
Ikeuchi
Toshihiko
T
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D016716:PC12 Cells / Q000187:drug effects; D010636:Phenols / Q000494:pharmacology*; D051381:Rats; D000091342:Endoplasmic Reticulum Chaperone BiP
D002614:Chelating Agents; D004533:Egtazic Acid; D006360:Heat-Shock Proteins; D048052:Mitogen-Activated Protein Kinase 3; D018832:Molecular Chaperones; D020932:Nerve Growth Factor; D010636:Phenols; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C025256:nonylphenol; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid