Inhibition of Constitutive NF-κB Activation in Mantle Cell Lymphoma B Cells Leads to Induction of Cell Cycle Arrest and Apoptosis

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Abstract
Constitutive activation of the NF-κB 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-κB 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-κB is constitutively activated in both the MCL cell lines and in the MCL patient biopsy cells. Since NF-κB has been shown to play an important role in a variety of cellular processes, including cell cycle regulation and apoptosis, targeting the NF-κB pathways for therapy may represent a rational approach in this malignancy. In the MCL cell lines, inhibition of constitutive NF-κB by the proteasome inhibitor PS-341 or a specific pIκBα inhibitor, BAY 11-7082, led to cell cycle arrest in G1 and rapid induction of apoptosis. Apoptosis was associated with the down-regulation of bcl-2 family members bcl-xL 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 G1 cell cycle arrest was associated with the inhibition of cyclin D1 expression, a molecular genetic marker of MCL. These studies suggest that constitutive NF-κB 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.