Central Role of Fas-associated Death Domain Protein in Apoptosis Induction by the Mitogen-activated Protein Kinase Kinase Inhibitor CI-1040 (PD184352) in Acute Lymphocytic Leukemia Cells in Vitro

Xue Wei Meng, Joya Chandra, David Loegering, Keri Van Becelaere, Timothy J. Kottke, Steven D. Gore, Judith Karp, Judy Sebolt-Leopold, Scott H. Kaufmann

Research output: Contribution to journalArticle

Abstract

Because the MAPK pathway plays important roles in cell proliferation and inhibition of apoptosis, this pathway has emerged as a potential therapeutic target for solid tumors and leukemia. At the present time there is little information about activation of this pathway and the consequences of its inhibition in acute lymphocytic leukemia cells (ALL). In the present study, constitutive MAPK pathway activation, as evidenced by phosphorylation of ERK1 and ERK2, was observed in 8 of 8 human lymphoid cell lines and 33% (8:24) of pretreatment ALL bone marrows. Inhibition of this pathway by the MEK inhibitors CI-1040 and PD098059 induced apoptosis through a unique pathway involving dephosphorylation and aggregation of Fas-associated death domain protein followed by death receptor-independent caspase-8 activation. Jurkat cell variants lacking Fas-associated death domain protein or procaspase-8 were resistant to CI-1040-induced apoptosis, as were Jurkat or Molt3 cells treated with the O-methyl ester of the caspase-8 inhibitor N-(Nα -benzyloxycarbonylisoleucylglutamyl) aspartate fluoromethyl ketone. In contrast, CI-1040-induced apoptosis was unaffected by blocking anti-Fas antibody, soluble tumor necrosis factor-α-related apoptosis-inducing ligand decoy receptor, or transfection with cDNA encoding the anti-apoptotic Bcl-2 family member Mcl-1 or dominant negative caspase-9. Collectively, these results identify the MAPK pathway as a potential therapeutic target in ALL and delineate a mechanism by which MEK inhibition triggers apoptosis in ALL cells.

Original languageEnglish (US)
Pages (from-to)47326-47339
Number of pages14
JournalJournal of Biological Chemistry
Volume278
Issue number47
DOIs
StatePublished - Nov 21 2003

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Fas-Associated Death Domain Protein
Mitogen-Activated Protein Kinase Kinases
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Apoptosis
Caspase 8
Chemical activation
Death Domain Receptors
Phosphorylation
Blocking Antibodies
Caspase Inhibitors
Jurkat Cells
Caspase 9
Cell proliferation
Ketones
Aspartic Acid
Bone Marrow Cells
Transfection
2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
In Vitro Techniques
Tumors

ASJC Scopus subject areas

  • Biochemistry

Cite this

Central Role of Fas-associated Death Domain Protein in Apoptosis Induction by the Mitogen-activated Protein Kinase Kinase Inhibitor CI-1040 (PD184352) in Acute Lymphocytic Leukemia Cells in Vitro. / Meng, Xue Wei; Chandra, Joya; Loegering, David; Van Becelaere, Keri; Kottke, Timothy J.; Gore, Steven D.; Karp, Judith; Sebolt-Leopold, Judy; Kaufmann, Scott H.

In: Journal of Biological Chemistry, Vol. 278, No. 47, 21.11.2003, p. 47326-47339.

Research output: Contribution to journalArticle

Meng, Xue Wei ; Chandra, Joya ; Loegering, David ; Van Becelaere, Keri ; Kottke, Timothy J. ; Gore, Steven D. ; Karp, Judith ; Sebolt-Leopold, Judy ; Kaufmann, Scott H. / Central Role of Fas-associated Death Domain Protein in Apoptosis Induction by the Mitogen-activated Protein Kinase Kinase Inhibitor CI-1040 (PD184352) in Acute Lymphocytic Leukemia Cells in Vitro. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 47. pp. 47326-47339.
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abstract = "Because the MAPK pathway plays important roles in cell proliferation and inhibition of apoptosis, this pathway has emerged as a potential therapeutic target for solid tumors and leukemia. At the present time there is little information about activation of this pathway and the consequences of its inhibition in acute lymphocytic leukemia cells (ALL). In the present study, constitutive MAPK pathway activation, as evidenced by phosphorylation of ERK1 and ERK2, was observed in 8 of 8 human lymphoid cell lines and 33{\%} (8:24) of pretreatment ALL bone marrows. Inhibition of this pathway by the MEK inhibitors CI-1040 and PD098059 induced apoptosis through a unique pathway involving dephosphorylation and aggregation of Fas-associated death domain protein followed by death receptor-independent caspase-8 activation. Jurkat cell variants lacking Fas-associated death domain protein or procaspase-8 were resistant to CI-1040-induced apoptosis, as were Jurkat or Molt3 cells treated with the O-methyl ester of the caspase-8 inhibitor N-(Nα -benzyloxycarbonylisoleucylglutamyl) aspartate fluoromethyl ketone. In contrast, CI-1040-induced apoptosis was unaffected by blocking anti-Fas antibody, soluble tumor necrosis factor-α-related apoptosis-inducing ligand decoy receptor, or transfection with cDNA encoding the anti-apoptotic Bcl-2 family member Mcl-1 or dominant negative caspase-9. Collectively, these results identify the MAPK pathway as a potential therapeutic target in ALL and delineate a mechanism by which MEK inhibition triggers apoptosis in ALL cells.",
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