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Rituximab (chimeric anti-CD20) sensitizes B-NHL cell lines to Fas-induced apoptosis

Oncogene volume 24, pages 8114–8127 (2005)Cite this article

Abstract

Rituximab (chimeric anti-CD20 monoclonal antibodies) is currently being used in the treatment of B non-Hodgkin's lymphoma (NHL). We have recently reported that rituximab triggers and modifies various intracellular signaling pathways in NHL B-cell lines, resulting in reverting the chemoresistant phenotype to a sensitive phenotype. This study investigated whether rituximab also modifies intracellular signaling pathways resulting in the sensitization of NHL cells to Fas-induced apoptosis. Treatment of the Fas-resistant NHL cell lines (2F7, Ramos and Raji) with rituximab sensitized the cells to CH-11 (FasL agonist mAb)-induced apoptosis and synergy was achieved. Fas expression was upregulated by rituximab as early as 6 h post-treatment as determined by flow cytometry, reverse transcriptase–polymerase chain reaction and Western blot. Rituximab inhibited both the expression and activity of the transcription repressor Yin-Yang 1 (YY1) that negatively regulates Fas transcription. Inhibition of YY1 resulted in the upregulation of Fas expression and sensitization of the tumor cells to CH-11-induced apoptosis. The downregulation of YY1 expression was the result of rituximab-induced inhibition of both the p38 mitogen-activated protein kinase (MAPK) signaling pathway and constitutive nuclear factor κ of B cells (NF-κB) activity. The involvement of NF-κB and YY1 in the regulation of Fas expression was corroborated by the use of Ramos cells with a dominant-active inhibitor of NF-κB (Ramos IκB-estrogen receptor (ER) mutant) and by silencing YY1 with YY1 siRNA, respectively. Further, the role of rituximab-mediated inhibition of the p38 MAPK/NF-κB/YY1 pathway in the regulation of Fas and sensitization to CH-11-induced apoptosis was validated by the use of specific chemical inhibitors of this pathway and which mimicked rituximab-mediated effects. These findings provide a novel mechanism of rituximab-mediated activity by sensitizing NHL cells to Fas-induced apoptosis.

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Abbreviations

ADCC:

antibody-dependent cellular cytotoxicity

ATCC:

American Tissue Cell Collection

Bay 11-7085:

(E)3-[(4-t-butylphenyl)sulfonyl]-2-propenenitrile

Bcl-2:

B-cell leukemia 2 protein

Bcl-xL:

Bcl-2-related gene

CDC:

complement-dependent cytotoxicity

DETA-NONOate:

(Z)-1-[2-(aminoethyl)-N-(2-ammonio-ethyl-amino]diazen-1-ium-1,2-diolate

DMSO:

dimethyl sulfoxide

EMSA:

electrophoretic mobility shift assay

FBS:

fetal bovine serum

IFN-γ:

interferon-γ

IgG:

immunoglobulin G

IKK:

IκB kinase complex

MAPK:

mitogen-activated protein kinase

MFI:

mean fluorescence intensity

NF-κB:

nuclear factor κ of B cells

NHL:

non-Hodgkin's lymphoma

NP40:

nonidet P40; octylphenoxypolyethoxyerthanol; polyethyleneglycol-p-isooctylphenyl ether

NO:

nitric oxide

PBS:

phosphate-buffered saline

PC-3:

prostate cancer cell line-3

PP2:

AG 1879; 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine

PI:

propidium iodide

PARP:

poly-(ADP-ribose) polymerase

RT–PCR:

reverse transcriptase–polymerase chain reaction

SB203580:

[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole]

SDS:

sodium dodecyl sulfate

Smac/DIABLO:

second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low PI

Sp1:

Sp transcription factor family

Src:

Rous sarcoma oncogene cellular homolog

U:

unit

YY1:

transcriptor factor Yin-Yang 1

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Acknowledgements

This project was funded in part by Fogarty Fellowships (D43 TW00013-14) (SH-Y, MV, UC Contacyt Nexus (SH-Y)), Jonsson Comprehensive Cancer Center (MV, AJ), and the UCLA AIDS Institute, UCLA Center for AIDS Research (AI28697) and State of California Universitywide AIDS Research Program (CC02-LA-001). We acknowledge Dr Paul Chinn, Biogen Idec pharmaceuticals for the CH2− rituximab. We also thank Kate Dinh, Christine Yue and Pearl Chan for their assistance in the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Microbiology, Immunology and Molecular Genetics, University of California, 10833 Le Conte Avenue, A2-060 CHS, Los Angeles, 90095, CA, USA

    Mario I Vega, Sara Huerta-Yepez, Ali R Jazirehi, Hermes Garban & Benjamin Bonavida

  2. Unidad de Investigaction Medica en Inmunologia e Infectologia, Hospital de Infectologia, CMN ‘La Raza’, IMSS, Mexico

    Mario I Vega & Sara Huerta-Yepez

  3. Department of Molecular and Medical Pharmacology, Jonnson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, 90095, Los Angeles, CA, USA

    Hermes Garban

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  1. Mario I Vega
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Correspondence to Benjamin Bonavida.

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Vega, M., Huerta-Yepez, S., Jazirehi, A. et al. Rituximab (chimeric anti-CD20) sensitizes B-NHL cell lines to Fas-induced apoptosis. Oncogene 24, 8114–8127 (2005). https://doi.org/10.1038/sj.onc.1208954

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