Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis.
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.
Pham
Lan V
LV
Department of Hematopathology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Tamayo
Archito T
AT
Yoshimura
Linda C
LC
Lo
Piao
P
Ford
Richard J
RJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D001706:Biopsy; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015778:Minor Histocompatibility Antigens; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009570:Nitriles; D009930:Organic Chemicals; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D013450:Sulfones; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000970:Antineoplastic Agents; C096816:BCL2-related protein A1; C494811:BCL2L1 protein, human; D001897:Boronic Acids; D006131:Growth Inhibitors; D020672:I-kappa B Proteins; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009570:Nitriles; D009930:Organic Chemicals; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D013450:Sulfones; D051020:bcl-X Protein; D000072000:NF-KappaB Inhibitor alpha; D000069286:Bortezomib