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2016 ; 7
(40
): 64886-64899
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An oncogenic role for sphingosine kinase 2
#MMPMID27588496
Neubauer HA
; Pham DH
; Zebol JR
; Moretti PA
; Peterson AL
; Leclercq TM
; Chan H
; Powell JA
; Pitman MR
; Samuel MS
; Bonder CS
; Creek DJ
; Gliddon BL
; Pitson SM
Oncotarget
2016[Oct]; 7
(40
): 64886-64899
PMID27588496
show ga
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.
|Apoptosis
[MESH]
|Carcinogenesis
[MESH]
|Cell Membrane/*metabolism
[MESH]
|Cell Nucleus/*metabolism
[MESH]
|Cell Proliferation
[MESH]
|Cell Survival
[MESH]
|Ceramides/metabolism
[MESH]
|Gene Expression Regulation, Neoplastic
[MESH]
|HEK293 Cells
[MESH]
|Humans
[MESH]
|Lysophospholipids/metabolism
[MESH]
|Phosphotransferases (Alcohol Group Acceptor)/genetics/*metabolism
[MESH]