title: Induction of apoptotic death and retardation of neuronal differentiation of human neural stem cells by sodium arsenite treatment.
abstract: Chronic arsenic toxicity is a global health problem that affects more than 100 million people worldwide. Long-term health effects of inorganic sodium arsenite in drinking water may result in skin, lung and liver cancers and in severe neurological abnormalities. We investigated in the present study whether sodium arsenite affects signaling pathways that control cell survival, proliferation and neuronal differentiation of human neural stem cells (NSC). We demonstrated that the critical signaling pathway, which was suppressed by sodium arsenite in NSC, was the protective PI3K-AKT pathway. Sodium arsenite (2-4μM) also caused down-regulation of Nanog, one of the key transcription factors that control pluripotency and self-renewal of stem cells. Mitochondrial damage and cytochrome-c release induced by sodium arsenite exposure was followed by initiation of the mitochondrial apoptotic pathway in NSC. Beside caspase-9 and caspase-3 inhibitors, suppression of JNK activity decreased levels of arsenite-induced apoptosis in NSC. Neuronal differentiation of NSC was substantially inhibited by sodium arsenite exposure. Overactivation of JNK1 and ERK1/2 and down-regulation of PI3K-AKT activity induced by sodium arsenite were critical factors that strongly affected neuronal differentiation. In conclusion, sodium arsenite exposure of human NSC induces the mitochondrial apoptotic pathway, which is substantially accelerated due to the simultaneous suppression of PI3K-AKT. Sodium arsenite also negatively affects neuronal differentiation of NSC through overactivation of MEK-ERK and suppression of PI3K-AKT.
authors.affiliation: Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, NY 10032, USA. vni3@columbia.edu
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Ivanov
authors.forename: Tom K
authors.initials: TK
authors.lastname: Hei
mesh_terms: D017209:Apoptosis; D018053:Arsenites / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D049109:Cell Proliferation; D002470:Cell Survival; D002867:Chromones / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009025:Morpholines / Q000494:pharmacology; D000071317:Nanog Homeobox Protein; D058953:Neural Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017670:Sodium Compounds / Q000494:pharmacology*; D014158:Transcription, Genetic
chemical_list: D018053:Arsenites; D053148:Caspase 3; D053181:Caspase 8; D061945:Caspase Inhibitors; D002867:Chromones; D045304:Cytochromes c; D018398:Homeodomain Proteins; D009025:Morpholines; D000071317:Nanog Homeobox Protein; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017670:Sodium Compounds; C486780:NANOG protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C017947:sodium arsenite; C505407:CASP3 protein, human; C505530:CASP8 protein, human