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.
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-(Nalpha-benzyloxycarbonylisoleucylglutamyl) aspartate fluoromethyl ketone. In contrast, CI-1040-induced apoptosis was unaffected by blocking anti-Fas antibody, soluble tumor necrosis factor-alpha-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.
Meng
Xue Wei
XW
Division of Oncology Research, Guggenheim 1342C, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Chandra
Joya
J
Loegering
David
D
Van Becelaere
Keri
K
Kottke
Timothy J
TJ
Gore
Steven D
SD
Karp
Judith E
JE
Sebolt-Leopold
Judy
J
Kaufmann
Scott H
SH
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D019281:Dimerization; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; D002352:Carrier Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases