Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis

• Published in: The Journal of immunology (1950) 2003-07, Vol.171 (1), p.88-95
• Main Authors: Pham, Lan V, Tamayo, Archito T, Yoshimura, Linda C, Lo, Piao, Ford, Richard J
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; B-Lymphocyte Subsets - drug effects; B-Lymphocyte Subsets - metabolism; B-Lymphocyte Subsets - pathology; bcl-X Protein; 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 - metabolism; Lymphoma, B-Cell - pathology; Lymphoma, Mantle-Cell - drug therapy; Lymphoma, Mantle-Cell - metabolism; Lymphoma, Mantle-Cell - pathology; Minor Histocompatibility Antigens; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; Nitriles; Organic Chemicals; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - metabolism; Pyrazines - pharmacology; Sulfones; Tumor Cells, Cultured
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.171.1.88

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.