期刊
PIGMENT CELL & MELANOMA RESEARCH
卷 28, 期 2, 页码 171-183出版社
WILEY-BLACKWELL
DOI: 10.1111/pcmr.12326
关键词
FTY720; vacuolar H+-ATPase; melanoma; sphingosine 1; phosphate receptor
资金
- Cancer Council NSW (CCNSW) [RG13-15, RG13-04]
- National Health and Medical Research Council (NHMRC)
- NHMRC
- Hunter Medical Research Institute (HMRI)
- Cancer Institute NSW (CINSW)
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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