Activation of p38 Mitogen-Activated Protein Kinase Is Required for Death Receptor–Independent Caspase-8 Activation and Cell Death in Response to Sphingosine
Sphingosine induces activation of multiple signaling pathways that play critical roles in controlling cell death. However, the precise molecular mechanism of cell death induced by sphingosine remains to be clarified. In this study, we show that sphingosine induces death receptor–independent caspase-...
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Published in | Molecular cancer research Vol. 7; no. 3; pp. 361 - 370 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Association for Cancer Research
01.03.2009
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Subjects | |
Online Access | Get full text |
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Summary: | Sphingosine induces activation of multiple signaling pathways that play critical roles in controlling cell death. However,
the precise molecular mechanism of cell death induced by sphingosine remains to be clarified. In this study, we show that
sphingosine induces death receptor–independent caspase-8 activation and apoptotic cell death via p38 mitogen-activated protein
kinase (MAPK) activation and that suppression of the MAPK/extracellular signal–regulated kinase (ERK) kinase/ERK pathway by
protein phosphatase 2A (PP2A) is required for p38 MAPK activation. Treatment of cells with sphingosine induced suppression
of ERK and activation of p38 MAPK. Inhibition of p38 MAPK led to the marked suppression of death receptor–independent caspase-8
activation and subsequent cell death induced by sphingosine. Interestingly, pretreatment with phorbol 12-myristate 13-acetate
or transfection of MAPK/ERK kinase/ERK resulting in ERK activation completely attenuated sphingosine-induced p38 MAPK activation.
PP2A activity was additionally elevated on sphingosine treatment. Small interfering RNA targeting of PP2A effectively attenuated
sphingosine-induced p38 MAPK activation through restoration of ERK activity, suggesting PP2A-mediated opposing regulation
of ERK and p38 MAPK. Our findings clearly imply that activation of p38 MAPK promotes death receptor–independent activation
of caspase-8 and apoptotic cell death pathways, thus providing a novel cellular mechanism for the anticancer activity of sphingolipid
metabolites. (Mol Cancer Res 2009;7(3):361–70) |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1541-7786 1557-3125 |
DOI: | 10.1158/1541-7786.MCR-08-0069 |