ABSTRACT
Constitutive activation of the NF-kappaB has been documented to be involved in the pathogenesis of many human malignancies, including hemopoietic neoplasms. In this study, we examined the status of NF-kappaB in two non-Hodgkin's lymphoma cell lines derived from mantle cell lymphoma (MCL) samples and in patient MCL biopsy specimens by EMSA and confocal microscopic analysis. We observed that NF-kappaB is constitutively activated in both the MCL cell lines and in the MCL patient biopsy cells. Since NF-kappaB has been shown to play an important role in a variety of cellular processes, including cell cycle regulation and apoptosis, targeting the NF-kappaB pathways for therapy may represent a rational approach in this malignancy. In the MCL cell lines, inhibition of constitutive NF-kappaB by the proteasome inhibitor PS-341 or a specific pIkappaBalpha inhibitor, BAY 11-7082, led to cell cycle arrest in G(1) and rapid induction of apoptosis. Apoptosis was associated with the down-regulation of bcl-2 family members bcl-x(L) and bfl/A1, and the activation of caspase 3, that mediates bcl-2 cleavage, resulting in the release of cytochrome c from the mitochondria. PS-341or BAY 11-induced G(1) cell cycle arrest was associated with the inhibition of cyclin D1 expression, a molecular genetic marker of MCL. These studies suggest that constitutive NF-kappaB expression plays a key role in the growth and survival of MCL cells, and that PS-341 and BAY 11 may be useful therapeutic agents for MCL, a lymphoma that is refractory to most current chemotherapy regimens.
Subject(s)
Apoptosis , B-Lymphocyte Subsets/metabolism , B-Lymphocyte Subsets/pathology , Cell Cycle , Lymphoma, B-Cell/metabolism , Lymphoma, Mantle-Cell/metabolism , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Nitriles , Organic Chemicals , Sulfones , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , B-Lymphocyte Subsets/drug effects , Biopsy , Boronic Acids/pharmacology , Bortezomib , Cell Cycle/drug effects , Growth Inhibitors/pharmacology , Humans , Hydrolysis , I-kappa B Proteins/antagonists & inhibitors , I-kappa B Proteins/physiology , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/pathology , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/pathology , Minor Histocompatibility Antigens , NF-KappaB Inhibitor alpha , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2/metabolism , Pyrazines/pharmacology , Tumor Cells, Cultured , bcl-X ProteinABSTRACT
B cell lineage non-Hodgkin's lymphomas (NHL-B) are neoplastic B cells that show dysregulated B lymphocyte growth characteristics. Unlike normal B cells, aggressive NHL-B cells show constitutive expression of nuclear NF-kappaB by maintaining an assembled, scaffold-like signaling platform, called a Signalosome within the lipid raft microdomain, extending from the cell membrane. The CD40 Signalosome appears to be initiated through autochthonous production and cognate binding of CD154 (CD40L, gp39) to CD40 by the lymphoma cell. Constitutive expression of NF-kappaB in NHL-B can be downregulated by treatment with antibodies to CD40 or CD154 that disrupt Signalosomes, inhibit lymphoma cell growth, and induce cell death. CD40 Signalosomes may provide a potentially vulnerable target for therapeutic intervention in NHL-B cells.
