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Involvement of vacuolar H + ‐ ATP ase in killing of human melanoma cells by the sphingosine kinase analogue FTY 720
Author(s) -
Tay Kwang Hong,
Liu Xiaoying,
Chi Mengna,
Jin Lei,
Jiang Chen Chen,
Guo Su Tang,
Verrills Nicole M.,
Tseng HsinYi,
Zhang Xu Dong
Publication year - 2015
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12326
Subject(s) - sphingosine kinase , sphingosine , microbiology and biotechnology , sphingosine 1 phosphate , autophagy , melanoma , sphingosine kinase 1 , kinase , protein kinase a , lysosome , chemistry , biology , cancer research , receptor , biochemistry , apoptosis , enzyme
Summary Targeting the sphingosine 1‐phosphate (S1P)/S1P receptor (S1 PR ) 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 FTY 720 that functionally antagonises S1 PR s kills human melanoma cells through a mechanism involving the vacuolar H + ‐ ATP ase activity. Moreover, we demonstrate that FTY 720‐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 FTY 720 and its analogues are promising candidates for further development as new therapeutic agents in the treatment of melanoma.