Abstract
The addition of rituximab (RTX) to standard chemotherapy has improved the treatment of B-cell malignancies. We show here that RTX and dexamethasone (Dex) induced synergistic apoptosis in follicular lymphoma cell lines. However, apoptosis was delayed by RTX-induced early protective signaling. RTX-induced early signaling also decreased Dex-induced apoptosis and led to phosphorylation of ERK1/2, Bcl-2 (at serine 70) and phosphorylation/degradation of BimL/EL. All these events were prevented by the MEK inhibitor, UO126. Therefore, we suggest that RTX-induced ERK-mediated signaling events lead to protection from apoptosis during early signaling and that blocking of Bim and Bcl-2 phosphorylation might be used as a novel strategy for lymphoma treatment.
Keywords:
Bim; Rituximab; apoptosis; dexamethasone; follicular lymphoma.
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Apoptosis / genetics*
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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Cell Line, Tumor
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Dexamethasone / pharmacology*
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Dose-Response Relationship, Drug
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Drug Synergism
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Humans
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Lymphoma, Follicular / metabolism*
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Membrane Proteins / metabolism
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Mitochondria / drug effects
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Mitochondria / metabolism
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Models, Biological
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Rituximab / pharmacology*
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Signal Transduction / drug effects*
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Membrane Proteins
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Rituximab
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Dexamethasone
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3