Involvement of extracellular signal-regulated kinases 1/2 and (phosphoinositide 3-kinase)/Akt signal pathways in acquired resistance against neurotoxin of 6-hydroxydopamine in SH-SY5Y cells following cell-cell interaction with astrocytes.
Glial cells interact with neurons and play important roles in the development, differentiation, maintenance and repair of the nervous system. Human neuroblastoma cells (SH-SY5Y) became dramatically resistant to neurotoxin 6-hydroxydopamine (6-OHDA), when co-cultured with mouse astrocytes. In order to further delineate the molecular mechanism involved in the neuroprotection in this selective cell-cell interaction, we assessed the activation of two signal pathways, namely, the MAP kinases (extracellular signal-regulated kinases, ERK1/2) and phosphoinositide 3-kinase (PI3-K)/Akt signal pathways in response to 6-OHDA insult and subsequent neuronal survival. Western blot revealed that 6-OHDA significantly increased the phosphorylation of ERK1/2 and Akt in mono-cultured SH-SY5Y cells. However, the increase in ERK1/2 in SH-SY5Y cells after co-cultured with astrocytes occurred as early as 3 h after 6-OHDA treatment in oppose to the increase after 12 h in monocultures. The phosphorylation of Akt in the co-cultured SH-SY5Y cells was much pronounced 3 h after 6-OHDA treatment compared with that in the mono-cultured cells. The anti-apoptotic protein bcl-2 was also increased in the co-cultured SH-SY5Y cells 3 h after treatment with 6-OHDA. Selective inhibitor of PI3-K/Akt signal pathway blocked the acquired resistance to 6-OHDA in SH-SY5Y cells following interaction with astrocytes. Inhibition of ERK1/2 signal pathway did not affect the cell survival. Our data suggest that PI3-K/Akt signal pathway, but not ERK1/2, is involved the acquired resistance in SH-SY5Y cells following cell-cell interaction with astrocytes against the neurotoxic 6-OHDA insult.
Jiang
Z
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Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E4.
Yu
P H
PH
D018663:Adrenergic Agents / Q000633:toxicity; D001253:Astrocytes / Q000502:physiology*; D015153:Blotting, Western / Q000379:methods; D002450:Cell Communication / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques / Q000379:methods; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009447:Neuroblastoma; D016627:Oxidopamine / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
D018663:Adrenergic Agents; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016627:Oxidopamine; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases