Journal
ONCOTARGET
Volume 6, Issue 13, Pages 11614-11626Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3426
Keywords
FTY720; TRAIL; DR5; Mcl-1; apoptosis
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Funding
- NRF - Korea Government (MSIP) [2014R1A5A2010008, NRF-2013R1A1A3009413]
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FTY720, Fingolimod, is a functional antagonist to the sphingosine-1-phoaphate (S1P) receptor and an inhibitor of sphingosine kinase 1. Here, we showed that a combination of FTY720 and TRAIL induced apoptosis in human renal, breast, and colon carcinoma cells. Most importantly, this combination had no effect on normal cells. Furthermore, the combined treatment with FTY720 and TRAIL reduced tumor growth in xenograft models. FTY720 up-regulated death receptor (DR) 5 at post-translational level. Knockdown of DR5 markedly blocked apoptosis induced by the combined treatment. FTY720 also inhibited Mcl-1 expression at the post-translational level. Over-expression of Mcl-1 blocked apoptosis induced by FTY720 and TRAIL. Interestingly, phospho-FTY720 and inhibitors of sphingosine kinase failed to enhance TRAIL-induced apoptosis. Thus, FTY720 enables TRAIL-induced apoptosis through up-regulation of DR5 and down-regulation of Mcl-1 in human cancer cells.
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