Abstract
FTY720, Fingolimod, is a functional antagonist to the sphingosine-1-phosphate (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.
Highlights
Sphingosine-1-phosphate (S1P) increases cancer cell proliferation [1, 2] and tumorigenesis [3, 4] and reduces cancer cell death [5]
We found that the mechanism of FTY720-mediated Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitization is associated with the up-regulation of DR5 protein stability and down-regulation of Mcl-1 protein stability
These findings suggest that FTY720 could be an attractive drug for TRAIL-sensitization
Summary
Sphingosine-1-phosphate (S1P) increases cancer cell proliferation [1, 2] and tumorigenesis [3, 4] and reduces cancer cell death [5]. Phospho-FTY720 binds sphingosine-1-phosphate (S1P) receptors and induces the internalization of S1P receptors. Phospho-FTY720 binds S1P1 and inhibits T lymphocyte egress from secondary lymphoid organs and migration into the transplanted graft, thereby suppressing inflammation [8]. FTY720 induces cell death in multiple cancer cells, including cells from leukemia [9, 10], prostate [11], ovarian [12], and pancreatic [13] lines. FTY720 sensitizes prostate cancer cells to radiotherapy [14], melanoma cells to cisplatin [15], and colon cancer cells to doxorubicin and etoposide [16]. The induction of protein phosphatase 2A [17], phospholipase C [18], and protein kinase C (PKC) activity was proposed to be involved in anti-cancer effects by FTY720
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