Involvement of vacuolar H+‐ATPase in killing of human melanoma cells by the sphingosine kinase analogue FTY720 |
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Authors: | Kwang Hong Tay Xiaoying Liu Mengna Chi Lei Jin Chen Chen Jiang Su Tang Guo Nicole M Verrills Hsin‐Yi Tseng Xu Dong Zhang |
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Institution: | 1. School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia;2. School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia |
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Abstract: | Targeting the sphingosine 1‐phosphate (S1P)/S1P receptor (S1PR) signalling axis is emerging as a promising strategy in the treatment of cancer. However, the effect of such an approach on survival of human melanoma cells remains less understood. Here, we show that the sphingosine analogue FTY720 that functionally antagonises S1PRs kills human melanoma cells through a mechanism involving the vacuolar H+‐ATPase activity. Moreover, we demonstrate that FTY720‐triggered cell death is characterized by features of necrosis and is not dependent on receptor‐interacting protein kinase 1 or lysosome cathepsins, nor was it associated with the activation of protein phosphatase 2A. Instead, it is mediated by increased production of reactive oxygen species and is antagonized by activation of autophagy. Collectively, these results suggest that FTY720 and its analogues are promising candidates for further development as new therapeutic agents in the treatment of melanoma. |
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Keywords: | FTY720 vacuolar H+‐ATPase melanoma sphingosine 1‐phosphate receptor |
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