Research Papers:
FTY720 enhances TRAILmediated apoptosis by upregulating DR5 and downregulating Mcl1 in cancer cells
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Seon Min Woo1, Bo Ram Seo1, Kyoung-jin Min1, Taeg Kyu Kwon1
1Department of Immunology, School of Medicine, Keimyung University, Dalseo-Gu, Daegu 704–701, South Korea
Correspondence to:
Kyoung-jin Min, e-mail: [email protected]
Taeg Kyu Kwon, e-mail: [email protected]
Keywords: FTY720, TRAIL, DR5, Mcl-1, apoptosis
Received: November 10, 2014 Accepted: February 24, 2015 Published: March 23, 2015
ABSTRACT
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.