1 Exposure of human mammary carcinoma cell line MCF-7 to TNF-a leads to apoptotic cell death within 24 h. In search for apoptosis-preventing signals, we identi®ed glucocorticoids as potent deathpreventing compounds. Ten nM dexamethasone provided a signi®cant protective e ect whereas 100 nM dexamethasone roughly blocked 80 ± 90% of TNF-a-induced apoptosis.2 Surprisingly, dexamethasone exerted a protective e ect even when supplied several hours after TNF-a. This points to a powerful inhibition of even advanced apoptotic processes by dexamethasone. 3 To further pinpoint the anti-apoptotic glucocorticoid action, we investigated the expression levels of several members of the inhibitors of apoptosis (IAPs) family of proteins in response to TNF-a and dexamethasone. IAP proteins directly block caspase protease activities including caspase-3, caspase-7, and caspase-9. Exposure of MCF-7 cells to TNF caused an extensive downregulation of cIAP1, cIAP2, and XIAP protein levels. The decline of the IAP protein levels temporally paralleled the appearance of apoptotic DNA fragments which started 12 ± 14 h following TNF-a addition and maximal e ects were seen within 24 h. 4 Coincubation of cells with TNF-a and dexamethasone potently blocked cIAP1, cIAP2, and XIAP downregulation. 5 TNF-a-mediated IAP protein downregulation was not a ected by proteasome inhibitors like lactacystin, ALLN or ALLM, whereas it was blocked by the broad-spectrum caspase inhibitor Z-VAD-fmk which also prevented TNF-a-induced apoptotic cell death. These data suggest that inhibition of IAP downregulation mediated by a caspase proteolytic activity constitutes the antiapoptotic action of glucocorticoids in MCF-7 carcinoma cells.
These data establish, to our knowledge for the first time, that RIAP1 mRNA levels are regulated by the cAMP-signaling pathway and suggest potential new avenues of therapy to modulate apoptosis.
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