Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non-Hodgkin's lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs.
Development of the chimeric mouse antihuman CD20 antibody, Rituximab, presented a notable advance in the treatment of patients with non-Hodgkin's lymphoma (NHL). Its use allowed the specific targeting of tumor B cells without the systemic toxicity of traditional therapies. The mechanisms by which Rituximab induces its antitumor activity are not fully understood. We have shown previously that Rituximab down-regulates Bcl-2 expression in some B-NHL cell lymphoma lines through an interleukin 10 (IL-10)-dependent autocrine loop, an effect that renders the resistant cells susceptible to chemotherapeutic drugs. The objective of this study was to delineate the signaling pathway by which Bcl-2 is controlled by Rituximab and IL-10. We hypothesized that the down-regulation of IL-10 by Rituximab decreases activation of the signal transducer and activator of transcription 3 (STAT3) protein, which in turn, is responsible for decreased levels of Bcl-2. We demonstrate by phosphoprotein immunoblotting and gel shift analyses that endogenous IL-10 induces activation of STAT3 in the 2F7 cell line. Furthermore, we show that Rituximab and anti-IL-10 antibody treatment decreases the ability of STAT3 to bind to its DNA binding site. The decrease in STAT3 activation by these treatments correlates with a decrease in Bcl-2 expression. Additionally, piceatannol, an inhibitor of STAT3 activation, down-regulates the expression of Bcl-2. Altogether, these results demonstrate that Bcl-2 expression is under the regulation of the STAT3 signaling pathway, which is regulated by endogenously secreted IL-10. Hence, Rituximab-induced down-regulation of IL-10 expression is responsible for the down-regulation of Bcl-2 and sensitization of NHL cells by therapeutic drugs. Furthermore, these findings support the notion that circulating IL-10 in vivo may control the resistance of NHL to drug-mediated cytotoxicity.
Alas
S
S
Department of Microbiology, Immunology and Molecular Genetics, Jonsson Comprehensive Cancer Center, University of California Los Angeles School of Medicine, University of California, Los Angeles, California 90095, USA.
Bonavida
B
B
D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002051:Burkitt Lymphoma / Q000378:metabolism / Q000628:therapy; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D000069283:Rituximab; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology
D000906:Antibodies; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013267:Stilbenes; D015534:Trans-Activators; D016753:Interleukin-10; D000069283:Rituximab; C041525:3,3',4,5'-tetrahydroxystilbene