The inhibitory mechanism of methylmercury on differentiation of human neuroblastoma cells.
Methylmercury (MeHg) is a ubiquitous environmental toxicant and shows neurotoxicity to central nerve system (CNS) or neuronal cells. It has been known that MeHg has more influence to developing or differentiating CNS/neuronal cells than adult or differentiated CNS/neuronal cells. This study examined the effect of MeHg on differentiation of human neuroblastoma SH-SY5Y cells induced by all-trans-retinoic acid (RA). MeHg caused the impairment of the RA-induced G(1/0) phase arrest; it was induced the reduction of G(1/0) phase and S phase arrest. Extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase C (PKC) are involved in the RA-mediated differentiation and cell cycle progression. Activation of ERK1/2 by RA was increased more in MeHg-treated differentiating cells, comparing with only RA-treated groups. Furthermore, in both cases of inhibition of ERK1/2 with PD98059 or inhibition of PKC with GF109203X, RA/MeHg-induced ERK1/2 phosphorylation was reduced and G(1/0) phase arrest was induced. Thus, it indicates that the neuronal differentiation with RA was mediated by the ERK1/2 and PKC related pathway and MeHg resulted in neurotoxic influences through the disturbance in steps of differentiation by this pathway. These results suggest that MeHg inhibits RA-induced differentiation in SH-SY5Y cells by a pathway dependent ERK1/2 and PKC.
Kim
Youn-Jung
YJ
Cellular and Molecular Toxicology Laboratory, Korea Institute of Science and Technology, Cheongryang, Seoul, Republic of Korea.
Kim
Young-Seok
YS
Kim
Mi-Soon
MS
Ryu
Jae-Chun
JC
D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007399:Interphase / Q000187:drug effects; D008301:Maleimides / Q000494:pharmacology; D008767:Methylmercury Compounds / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology
D005419:Flavonoids; D007211:Indoles; D008301:Maleimides; D008767:Methylmercury Compounds; D014212:Tretinoin; D051571:Protein Kinase C-alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C070515:bisindolylmaleimide I; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one