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- W142054775 abstract "Background: We have previously shown that the level of expression of death receptors for TRAIL, in particular TRAIL-R2 appeared an important determinant of TRAIL-induced apoptosis in melanoma cell lines. However, TRAIL induces low levels of apoptosis in some melanoma cell lines despite relative high levels of TRAIL-R2 expression on the cell surface. Objective: To elucidate the intracellular mechanisms that regulate the sensitivity of melanoma cells to TRAIL induced apoptosis. Methods: We examined the multiple checkpoints in the TRAIL-initiated apoptotic signalling pathway by flow cytometry, western blot, immunofluorescence staining. c-DNA for XIAP, Bcl-2 and Smac/DIABLO were transfected into TRAIL-sensitive or TRAIL-resistant melanoma cells, respectively, to confirm their role in regulation of TRAIL-induced apoptosis. Results: We identified four melanoma lines with high TRAIL-R2 expression but low sensitivity to TRAIL induced apoptosis. The lines were shown to have similar levels of TRAIL-induced activated caspase-3 as the TRAIL sensitive lines but substrates downstream of caspase-3 (ICAD and PARP) were not degraded in the insensitive cell lines. This appeared to be due to inhibition of caspase-3 by XIAP in that XIAP was bound to activated caspase-3 and transfection of XIAP results in inhibition of TRAIL induced apoptosis. Reduction of XIAP levels by pre-treatment with Actinomycin D or by specific inhibition of XIAP by overexpression of Smac/DIABLO in the resistant melanoma cells was associated with the appearance of catalytic activity by caspase-3, increased TRAIL-induced apoptosis and reduced XIAP levels. After exposure to TRAIL, XIAP levels were markedly reduced in the TRAIL sensitive compared to resistant lines. This appeared to be associated with Smac/DIABLO release from mitochondria as this release was greater in TRAIL sensitive compared to resistant lines and had similar kinetics to downregulation of XIAP levels. Furthermore, overexpression of Bcl-2 inhibited Smac/DIABLO release and downregulation of XIAP levels. These results indicate that inhibition of caspase-3 by XIAP appears an important mechanism for protection of melanoma cells from TRAIL-induced apoptosis and provide evidence that TRAIL induced Smac/DIABLO release from mitochondria is a key regulator of TRAIL induced apoptosis of melanoma." @default.
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- W142054775 date "2001-01-01" @default.
- W142054775 modified "2023-09-24" @default.
- W142054775 title "TRAIL Induced Apoptosis of Human Melanoma is Regulated by Smac/DIABLO Release from Mitochondria" @default.
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