FTY720 Induces Autophagy-Associated Apoptosis in Human Oral Squamous Carcinoma Cells, in Part, through a Reactive Oxygen Species/Mcl-1-Dependent Mechanism
Abstract In this study, we interrogated the mechanism by which the immunosuppressant FTY720 mediates anticancer effects in oral squamous cell carcinoma (OSCC) cells. FTY720 differentially suppressed the viability of the OSCC cell lines SCC4, SCC25, and SCC2095 with IC50 values of 6.1, 6.3, and 4.5 μ...
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| Autores principales: | , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2017
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/c320f44d950445378008bb0d47854a3b |
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| Sumario: | Abstract In this study, we interrogated the mechanism by which the immunosuppressant FTY720 mediates anticancer effects in oral squamous cell carcinoma (OSCC) cells. FTY720 differentially suppressed the viability of the OSCC cell lines SCC4, SCC25, and SCC2095 with IC50 values of 6.1, 6.3, and 4.5 μM, respectively. This antiproliferative effect was attributable to the ability of FTY720 to induce caspase-dependent apoptosis. Mechanistic evidence suggests that FTY720-induced apoptosis was associated with its ability to inhibit Akt-NF-κB signaling, to facilitate the proteasomal degradation of the antiapoptotic protein Mcl-1, and to increase reactive oxygen species (ROS) generation. Both overexpression of Mcl-1 and inhibition of ROS partially protected cells from FTY720-induced caspase-9 activation, PARP cleavage and cytotoxicity. In addition, FTY720 induced autophagy in OSCC cells, as manifested by LC3B-II conversion, decreased p62 expression, and accumulation of autophagosomes. Inhibition of autophagy by bafilomycin A1 protected cells from FTY720-induced apoptosis. Together, these findings suggest an intricate interplay between autophagy and apoptosis in mediating the tumor-suppressive effect in OSCC cells, which underlies the translational potential of FTY720 in fostering new therapeutic strategies for OSCC. |
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