Journal
BMB REPORTS
Volume 45, Issue 8, Pages 482-487Publisher
KOREAN SOCIETY BIOCHEMISTRY & MOLECULAR BIOLOGY
DOI: 10.5483/BMBRep.2012.45.8.024
Keywords
Bromocriptine; Calcium mobilization; Cyclosporine A; Endoplasmic reticulum stress
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Funding
- Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [A102059]
- NIH [R03 DA024887, R01 AG15393]
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To identify the novel inhibitors of endoplasmic reticulurn stress-induced cell death, we performed a high throughput assay with a chemical library containing a total of 3,280 bioactive small molecules. Cyclosporine A and bromocriptine were identified as potent inhibitors of thapsigargiin-induced cell death (cut-off at 4 sigma standard score). However, U74389G, the potent inhibitor of lipid peroxidation had lower activity in inhibiting cell death. The inhibition effect of cyclosporine A and bromocriptine was specific for only thapsigargin-induced cell death. The mechanism of inhibition by these compounds was identified as modification of the expression of glucose regulated protein-78 (GRP-78/Bip) and inhibition of phosphorylafion of p38 mitogen activated protein kinase (MAPK). However, these compounds did not inhibit the same events triggered by tunicamycin, which was in agreement with the cell survival data. We suggest that the induction of protective unfolded protein response by these compounds confers resistance to cell death. In summary, we identified compounds that may provide insights on cell death mechanisms stimulated by ER stress. [BMB Reports 2012; 45(8): 482-487]
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