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-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.
Yoon
Chang-Hwan
CH
Department of Chemistry, Hanyang University, Seoul, Korea.
Kim
Min-Jung
MJ
Park
Moon-Taek
MT
Byun
Joo-Yun
JY
Choi
Young-Hyun
YH
Yoo
Hwan-Soo
HS
Lee
Yong-Moon
YM
Hyun
Jin-Won
JW
Lee
Su-Jae
SJ
D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism; D034741:RNA, Small Interfering; D053218:Receptors, Death Domain / Q000378:metabolism*; D013110:Sphingosine / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D034741:RNA, Small Interfering; D053218:Receptors, Death Domain; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2; D053181:Caspase 8; D013110:Sphingosine