Abstract
We have recently shown that proteasome inhibitor PS-341 induces apoptosis in drug-resistant multiple myeloma (MM) cells, inhibits binding of MM cells in the bone marrow microenvironment, and inhibits cytokines mediating MM cell growth, survival, drug resistance, and migration in vitro. PS-341 also inhibits human MM cell growth and prolongs survival in a SCID mouse model. Importantly, PS-341 has achieved remarkable clinical responses in patients with refractory relapsed MM. We here demonstrate molecular mechanisms whereby PS-341 mediates anti-MM activity by inducing p53 and MDM2 protein expression; inducing the phosphorylation (Ser15) of p53 protein; activating c-Jun NH(2)-terminal kinase (JNK), caspase-8, and caspase-3; and cleaving the DNA protein kinase catalytic subunit, ATM, and MDM2. Inhibition of JNK activity abrogates PS-341-induced MM cell death. These studies identify molecular targets of PS-341 and provide the rationale for the development of second-generation, more targeted therapies.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antineoplastic Agents / pharmacology*
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Ataxia Telangiectasia Mutated Proteins
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Boronic Acids / pharmacology*
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Boronic Acids / therapeutic use
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Bortezomib
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Caspase 3
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Caspase 8
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Caspase 9
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Caspases / metabolism
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Cell Cycle Proteins
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Cell Death / drug effects
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DNA-Activated Protein Kinase
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DNA-Binding Proteins*
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Enzyme Activation / drug effects
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Gene Expression / drug effects
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Humans
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JNK Mitogen-Activated Protein Kinases*
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology
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Nuclear Proteins*
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Phosphorylation
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Phosphoserine / metabolism
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Protease Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-mdm2
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Pyrazines / pharmacology*
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Pyrazines / therapeutic use
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins
Substances
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Antineoplastic Agents
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Boronic Acids
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Cell Cycle Proteins
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DNA-Binding Proteins
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Nuclear Proteins
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Protease Inhibitors
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Proto-Oncogene Proteins
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Pyrazines
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Phosphoserine
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Bortezomib
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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DNA-Activated Protein Kinase
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PRKDC protein, human
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Protein Serine-Threonine Kinases
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases
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CASP3 protein, human
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CASP8 protein, human
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CASP9 protein, human
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Casp3 protein, mouse
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Casp8 protein, mouse
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Casp9 protein, mouse
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Caspase 3
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Caspase 8
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Caspase 9
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Caspases