Basic fibroblast growth factor-induced cell death is effected through sustained activation of p38MAPK and up-regulation of the death receptor p75NTR.
Basic fibroblast growth factor (bFGF) induces cell death in cells of the Ewing's sarcoma family of tumors in vivo and in vitro. In this study we demonstrate that this is dependent on the rapid and sustained activation of p38(MAPK), in contrast to the transient activation of p38(MAPK) associated with bFGF-induced cell proliferation. Stem cell factor-induced survival of TC-32 cells was also associated with transient activation of p38(MAPK). Inhibition of p38(MAPK) by SB202190 and p38(MAPK) small interfering RNA reduces bFGF-induced death in TC-32 cells, consistent with the hypothesis that activation of p38(MAPK) is essential for induction of death by bFGF. This appears to be dependent on sustained activation of p38(MAPK), demonstrated by inhibition of bFGF-induced cell death following addition of SB202190 to TC-32 cells 5 min after exposure to bFGF (20 ng/ml) and activation of p38(MAPK). Prolonged activation of p38(MAPK) is accompanied by a rapid and sustained phosphorylation of Ras and ERK; inhibition of ERK phosphorylation using the MEK-1 inhibitor PD98059 rescued approximately 30% of cells from bFGF-induced death suggesting ERK plays a secondary role in the induction of death. This hypothesis is supported by observations in the A673 cell line; bFGF induced sustained activation of ERK and transient activation of p38(MAPK), which was not associated with cell death. These data demonstrate that sustained activation of p38(MAPK) is essential for activation of the death cascade following exposure of Ewing's sarcoma family of tumors cells to bFGF and provide evidence that activation of p38(MAPK) results in an up-regulation of the death receptor p75(NTR).
Candlelighter's Children's Cancer Research Laboratory, Cancer Research UK Clinical Centre, St. James's University Hospital, Leeds LS9 7TF, United Kingdom.
Andrew J K
AJ
Williamson
Benjamin C
BC
Dibling
James R
JR
Boyne
Peter
P
Selby
Susan A
SA
Burchill
D000818:Animals; D016923:Cell Death / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019089:Stem Cell Factor / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D011993:Recombinant Fusion Proteins; D019089:Stem Cell Factor; D016222:Fibroblast Growth Factor 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins