Sphingosine kinase-1 is a downstream regulator of imatinib-induced apoptosis in chronic myeloid leukemia cells View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2008-05

AUTHORS

E Bonhoure, A Lauret, D J Barnes, C Martin, B Malavaud, T Kohama, J V Melo, O Cuvillier

ABSTRACT

We examined the involvement of sphingosine kinase-1 (SphK1), which governs the ceramide/sphingosine-1-phosphate balance, in susceptibility to imatinib of either sensitive or resistant chronic myeloid leukemia cells. Imatinib-sensitive LAMA84-s displayed marked SphK1 inhibition coupled with increased content of ceramide and decreased pro-survival sphingosine-1-phosphate. Conversely, no changes in the sphingolipid metabolism were observed in LAMA84-r treated with imatinib. Overcoming imatinib resistance in LAMA84-r with farnesyltransferase or MEK/ERK inhibitors as well as with cytosine arabinoside led to SphK1 inhibition. Overexpression of SphK1 in LAMA84-s cells impaired apoptosis and inhibited the effects of imatinib on caspase-3 activation, cytochrome c and Smac release from mitochondria through modulation of Bim, Bcl-xL and Mcl-1 expression. Pharmacological inhibition of SphK1 with F-12509a or its silencing by siRNA induced apoptosis of both imatinib-sensitive and -resistant cells, suggesting that SphK1 inhibition was critical for apoptosis signaling. We also show that imatinib-sensitive and -resistant primary cells from chronic myeloid leukemia patients can be successfully killed in vitro by the F-12509a inhibitor. These results uncover the involvement of SphK1 in regulating imatinib-induced apoptosis and establish that SphK1 is a downstream effector of the Bcr-Abl/Ras/ERK pathway inhibited by imatinib but upstream regulator of Bcl-2 family members. More... »

PAGES

leu200895

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/leu.2008.95

DOI

http://dx.doi.org/10.1038/leu.2008.95

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1050897798

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/18401414


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Turtle is a human-readable linked data format.

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RDF/XML is a standard XML format for linked data.

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302 schema:name Department of Haematology, Imperial College London, Hammersmith Hospital, London, UK
303 rdf:type schema:Organization
 




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