Cytoplasmic dynein regulates the subcellular localization of sphingosine kinase 2 to elicit tumor-suppressive functions in glioblastoma

While the two mammalian sphingosine kinases, SK1 and SK2, both catalyze the generation of pro-survival sphingosine 1-phosphate (S1P), their roles vary dependent on their different subcellular localization. SK1 is generally found in the cytoplasm or at the plasma membrane where it can promote cell pr...

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Bibliographic Details
Published in:	Oncogene Vol. 38; no. 8; pp. 1151 - 1165
Main Authors:	Neubauer, Heidi A., Tea, Melinda N., Zebol, Julia R., Gliddon, Briony L., Stefanidis, Cassandra, Moretti, Paul A. B., Pitman, Melissa R., Costabile, Maurizio, Kular, Jasreen, Stringer, Brett W., Day, Bryan W., Samuel, Michael S., Bonder, Claudine S., Powell, Jason A., Pitson, Stuart M.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-02-2019 Nature Publishing Group
Subjects:	13/106 13/89 13/95 631/67/1922 631/80/86 64/60 82/111 82/51 Angiogenesis Animals Apoptosis Apoptosis - genetics Biochemistry Brain cancer Cancer Carcinogenesis Carcinogenesis - genetics Care and treatment Cell Biology Cell death Cell Line, Tumor Cell Membrane - genetics Cell membranes Cell proliferation Cell Proliferation - genetics Cell survival Cytoplasm Cytoplasmic Dyneins - genetics Development and progression Dynein Endoplasmic reticulum Enzymes Gene expression Gene Expression Regulation, Neoplastic Genes, Tumor Suppressor Genetic aspects Glioblastoma Glioblastoma - genetics Glioblastoma - pathology Glioblastomas Gliomas Health aspects HEK293 Cells Human Genetics Humans Internal Medicine Kinases Localization Lysophospholipids - genetics Medicine Medicine & Public Health Mice Mitochondria Oncology Phosphates Phosphotransferases (Alcohol Group Acceptor) - genetics Plasma Sphingosine Sphingosine - analogs & derivatives Sphingosine - genetics Sphingosine 1-phosphate Sphingosine kinase Tumor suppressor genes Tumorigenesis Tumors Xenograft Model Antitumor Assays
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Summary:	While the two mammalian sphingosine kinases, SK1 and SK2, both catalyze the generation of pro-survival sphingosine 1-phosphate (S1P), their roles vary dependent on their different subcellular localization. SK1 is generally found in the cytoplasm or at the plasma membrane where it can promote cell proliferation and survival. SK2 can be present at the plasma membrane where it appears to have a similar function to SK1, but can also be localized to the nucleus, endoplasmic reticulum or mitochondria where it mediates cell death. Although SK2 has been implicated in cancer initiation and progression, the mechanisms regulating SK2 subcellular localization are undefined. Here, we report that SK2 interacts with the intermediate chain subunits of the retrograde-directed transport motor complex, cytoplasmic dynein 1 (DYNC1I1 and -2), and we show that this interaction, particularly with DYNC1I1, facilitates the transport of SK2 away from the plasma membrane. DYNC1I1 is dramatically downregulated in patient samples of glioblastoma (GBM), where lower expression of DYNC1I1 correlates with poorer patient survival. Notably, low DYNC1I1 expression in GBM cells coincided with more SK2 localized to the plasma membrane, where it has been recently implicated in oncogenesis. Re-expression of DYNC1I1 reduced plasma membrane-localized SK2 and extracellular S1P formation, and decreased GBM tumor growth and tumor-associated angiogenesis in vivo. Consistent with this, chemical inhibition of SK2 reduced the viability of patient-derived GBM cells in vitro and decreased GBM tumor growth in vivo. Thus, these findings demonstrate a tumor-suppressive function of DYNC1I1, and uncover new mechanistic insights into SK2 regulation which may have implications in targeting this enzyme as a therapeutic strategy in GBM.
ISSN:	0950-9232 1476-5594
DOI:	10.1038/s41388-018-0504-9