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Cellular and molecular signal transduction pathways modulated by rituximab (rituxan, anti-CD20 mAb) in non-Hodgkin's lymphoma: implications in chemosensitization and therapeutic intervention

Oncogene volume 24, pages 2121–2143 (2005)Cite this article

Abstract

The clinical application of rituximab (chimeric mouse anti-human CD20 mAb, Rituxan, IDEC-C2B8), alone and/or combined with chemotherapy, has significantly ameliorated the treatment outcome of patients with relapsed and refractory low-grade or follicular non-Hodgkin's lymphoma (NHL). The exact in vivo mechanisms of action of rituximab are not fully understood, although antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis have been suggested. We have proposed that modifications of the cellular signaling pathways by rituximab may be crucial for its clinical response. The B-cell restricted cell surface phosphoprotein CD20 is involved in many cellular signaling events including proliferation, activation, differentiation, and apoptosis upon crosslinking. Monomeric rituximab chemosensitizes drug-resistant NHL cells via selective downregulation of antiapoptotic factors through the type II mitochondrial apoptotic pathway. Several signaling pathways are affected by rituximab which are implicated in the underlying molecular mechanisms of chemosensitization. ARL (acquired immunodeficiency syndrome (AIDS)-related lymphoma) and non-ARL cell lines have been examined as in vitro model systems. In ARL, rituximab diminishes the activity of the p38MAPK signaling pathway resulting in inhibition of the interleukin (IL)-10/IL-10R autocrine/paracrine cytokine autoregulatory loop leading to the inhibition of constitutive STAT-3 activity and subsequent downregulation of Bcl-2 expression leading to chemosensitization. Rituximab upregulates Raf-1 kinase inhibitor protein (RKIP) expression in non-ARL cells. Through physical association with Raf-1 and nuclear factor κB (NF-κB)-inducing kinase (NIK), RKIP negatively regulates two major survival pathways, namely, the extracellular signal-regulated kinase1/2 (ERK1/2) and the NF-κB pathways, respectively. Downmodulation of the ERK1/2 and NF-κB pathways inhibits the transcriptional activity of AP-1 and NF-κB transcription factors, respectively, both of which lead to the downregulation of Bcl-xL (Bcl-2 related gene (long alternatively spliced variant of Bcl-x gene)) transcription and expression and sensitization to drug-induced apoptosis. Bcl-xL-overexpressing cells corroborated the pivotal role of Bcl-xL in chemosensitization. The specificity of rituximab-mediated signaling and functional effects were corroborated by the use of specific pharmacological inhibitors. Many patients do not respond and/or relapse and the mechanisms of unresponsiveness are unknown. Rituximab-resistant B-NHL clones were generated to investigate the acquired resistance to rituximab-mediated signaling, and chemosensitization. Resistant clones display different phenotypic, genetic and functional properties compared to wild-type cells. This review summarizes the data highlighting a novel role of rituximab as a signal-inducing antibody and as a chemosensitizing agent through negative regulation of major survival pathways. Studies presented herein also reveal several intracellular targets modified by rituximab, which can be exploited for therapeutic and prognostic purposes in the treatment of patients with rituximab- and drug-refractory NHL.

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Abbreviations

ADCC:

antibody-dependent cell-mediated cytotoxicity

AP-1:

activator protein-1

ARL:

acquired immunodeficiency syndrome (AIDS)-related lymphoma

Bcl-2:

B-cell lymphoma protein 2

Bcl-xL:

Bcl-2 related gene (long alternatively spliced variant of Bcl-x gene)

CDC:

complement-dependent cytotoxicity

DHMEQ:

dehydroxy methylepoxy quinomicin

DLBCL:

diffuse large B-cell lymphoma

ERK1/2 MAPK:

extracellular signal-regulated kinase1/2 mitogen-activated protein kinase

IKK:

inhibitor of kappa B (IκB) kinase complex

IL:

interleukin

JNK/SAPK:

c-Jun NH2-terminal kinase/stress-activated protein kinase

MEK1/2:

mitogen-activated protein kinase kinase 1/2

2MAM-A3:

2-methoxyantimycin-A3

NIK:

nuclear factor κB (NF-κB)-inducing kinase

RKIP:

Raf-1 kinase inhibitor protein

STAT:

signal transducer and activator of transcription

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Acknowledgements

We acknowledge Doctor Gary Schiller (UCLA, Hematology/Oncology) for critical review of the manuscript and valuable insights, Doctors Mario Vega and Sara Huerta-Yepez for communicating their unpublished studies and Christine Yue for the preparation of the manuscript. This work was supported in part by a fellowship award from UCLA Jonsson Comprehensive Cancer Center (JCCC) (to ARJ).

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  1. Department of Microbiology, Immunology and Molecular Genetics, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, 90095-1747, USA

    Ali R Jazirehi & Benjamin Bonavida

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Jazirehi, A., Bonavida, B. Cellular and molecular signal transduction pathways modulated by rituximab (rituxan, anti-CD20 mAb) in non-Hodgkin's lymphoma: implications in chemosensitization and therapeutic intervention. Oncogene 24, 2121–2143 (2005). https://doi.org/10.1038/sj.onc.1208349

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