title: Involvement of vacuolar H(+)-ATPase in killing of human melanoma cells by the sphingosine kinase analogue FTY720.
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.
authors.affiliation: School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia.
authors.forename: Kwang Hong
authors.initials: KH
authors.lastname: Tay
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Liu
authors.forename: Mengna
authors.initials: M
authors.lastname: Chi
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: Chen Chen
authors.initials: CC
authors.lastname: Jiang
authors.forename: Su Tang
authors.initials: ST
authors.lastname: Guo
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Verrills
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Tseng
authors.forename: Xu Dong
authors.initials: XD
authors.lastname: Zhang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D000068876:Fingolimod Hydrochloride; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011409:Propylene Glycols / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism*; D000099157:Sphingosine Kinase
chemical_list: D000255:Adenosine Triphosphate; D004121:Dimethyl Sulfoxide; D000068876:Fingolimod Hydrochloride; D018942:Macrolides; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D054648:Protein Phosphatase 2; D017382:Reactive Oxygen Species; D013110:Sphingosine; D025262:Vacuolar Proton-Translocating ATPases; D000099157:Sphingosine Kinase; C040929:bafilomycin A1
keywords: FTY720; melanoma; sphingosine 1-phosphate receptor; vacuolar H+-ATPase