title: An oncogenic role for sphingosine kinase 2.
abstract: While both human sphingosine kinases (SK1 and SK2) catalyze the generation of the pleiotropic signaling lipid sphingosine 1-phosphate, these enzymes appear to be functionally distinct. SK1 has well described roles in promoting cell survival, proliferation and neoplastic transformation. The roles of SK2, and its contribution to cancer, however, are much less clear. Some studies have suggested an anti-proliferative/pro-apoptotic function for SK2, while others indicate it has a pro-survival role and its inhibition can have anti-cancer effects. Our analysis of gene expression data revealed that SK2 is upregulated in many human cancers, but only to a small extent (up to 2.5-fold over normal tissue). Based on these findings, we examined the effect of different levels of cellular SK2 and showed that high-level overexpression reduced cell proliferation and survival, and increased cellular ceramide levels. In contrast, however, low-level SK2 overexpression promoted cell survival and proliferation, and induced neoplastic transformation in vivo. These findings coincided with decreased nuclear localization and increased plasma membrane localization of SK2, as well as increases in extracellular S1P formation. Hence, we have shown for the first time that SK2 can have a direct role in promoting oncogenesis, supporting the use of SK2-specific inhibitors as anti-cancer agents.
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.|School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.
authors: Heidi A
authors: HA
authors: Neubauer
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.|School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.
authors: Duyen H
authors: DH
authors: Pham
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors: Julia R
authors: JR
authors: Zebol
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors: Paul A B
authors: PA
authors: Moretti
authors: Monash Institute of Pharmaceutical Science, Monash University, Parkville, Victoria, Australia.
authors: Amanda L
authors: AL
authors: Peterson
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors: Tamara M
authors: TM
authors: Leclercq
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.|School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.
authors: Huasheng
authors: H
authors: Chan
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.|School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors: Jason A
authors: JA
authors: Powell
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors: Melissa R
authors: MR
authors: Pitman
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.|School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors: Michael S
authors: MS
authors: Samuel
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.|School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.|School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors: Claudine S
authors: CS
authors: Bonder
authors: Monash Institute of Pharmaceutical Science, Monash University, Parkville, Victoria, Australia.
authors: Darren J
authors: DJ
authors: Creek
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors: Briony L
authors: BL
authors: Gliddon
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.|School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.|School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors: Stuart M
authors: SM
authors: Pitson
mesh_terms: D017209:Apoptosis; D063646:Carcinogenesis; D002462:Cell Membrane / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D002518:Ceramides / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D002518:Ceramides; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; C060506:sphingosine 1-phosphate; C000594250:sphingosine kinase 2, human; D000099157:Sphingosine Kinase
keywords: neoplastic transformation; oncogenesis; proliferation; sphingosine kinase 2; tumorigenesis