Research Papers:

FTY720 enhances TRAIL-mediated apoptosis by up-regulating DR5 and down-regulating Mcl-1 in cancer cells

Seon Min Woo _, Bo Ram Seo, Kyoung-jin Min and Taeg Kyu Kwon

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Oncotarget. 2015; 6:11614-11626. https://doi.org/10.18632/oncotarget.3426

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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


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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