Regulation of hairy-cell survival through constitutive activation of mitogen-activated protein kinase pathways.
The hairy cells (HCs) of hairy-cell leukemia are intrinsically activated mature clonal B cells. The aims of this study were to gain further insights into the nature of this activation and to assess its importance for the prolonged HC survival in this chronic disease. We show that HCs contain phosphorylated/activated p38 MAPK, JNK and ERK1/ERK2 (ERK1/2). PKC inhibitors increased the activation of p38 and JNK, but reduced the phosphorylation of ERK1/2. Moreover, PKC inhibition resulted in cell death; cell death was also observed when the activation of ERK1/2 in HCs was abrogated with an inhibitor of MEK1/2 activation. In addition to PKC, active Src kinase was also shown to be involved in the maintenance of Raf-independent ERK activation in HCs. During cell culture on a nonadherent surface, ERK phosphorylation was sustained, while phosphorylation of p38 and JNK decreased. This decrease was not observed in HCs cultured on vitronectin (VN), indicating that p38/JNK activation is probably a consequence of in vivo HC interaction with VN present in abundance in the red pulp of the spleen. Taken together, these results suggest that active p38/JNK make HCs susceptible to apoptosis, but the cells are effectively rescued by ERK activation involving constitutively active PKC and Src. These findings are relevant for the understanding of the prolonged cell survival of HCs and their selective sensitivity to some chemotherapeutic agents.
Kamiguti
Aura S
AS
Department of Haematology, Royal Liverpool University Hospital, University of Liverpool, UK. aurakami@liverpool.ac.uk
Harris
Robert J
RJ
Slupsky
Joseph R
JR
Baker
Peter K
PK
Cawley
John C
JC
Zuzel
Mirko
M
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology* / Q000201:enzymology; D002448:Cell Adhesion; D002470:Cell Survival; D017338:Cladribine / Q000494:pharmacology; D002999:Clone Cells / Q000166:cytology / Q000201:enzymology; D003470:Culture Media; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D007943:Leukemia, Hairy Cell / Q000201:enzymology / Q000473:pathology*; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009360:Neoplastic Cells, Circulating; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000201:enzymology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000201:enzymology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019096:Vitronectin; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases / Q000502:physiology
D000964:Antimetabolites, Antineoplastic; D003470:Culture Media; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009363:Neoplasm Proteins; D014409:Tumor Necrosis Factor-alpha; D019096:Vitronectin; D017338:Cladribine; C482128:MAP2K2 protein, human; D048056:Mitogen-Activated Protein Kinase 9; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D048670:MAP Kinase Kinase 4; C482125:MAP2K1 protein, human; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases