Rituximab inhibits p38 MAPK activity in 2F7 B NHL and decreases IL-10 transcription: pivotal role of p38 MAPK in drug resistance.
We have recently reported that Rituximab (anti-CD20) sensitizes drug-resistant 2F7 and 10C9 B Non-Hodgkin's lymphoma (NHL) cell lines to the apoptotic effects of various chemotherapeutic drugs by downregulation of IL-10 and Bcl-2 expression. The mechanism by which Rituximab induces downregulation of IL-10 was examined. We hypothesized that Rituximab may inhibit p38 MAPK activity that regulates IL-10 expression via Sp1. Treatment of 2F7 cells with Rituximab or the p38 inhibitor SB203580 inhibited the constitutive p38 MAPK activity and resulted in the inhibition of Sp1, IL-10, STAT3, and Bcl-2. Inhibition of the Src-family PTKs, Lyn, and Src-family PTKs upstream signaling molecules of the p38MAPK pathway, by PP2, a specific Src-family kinase inhibitor, resulted in the inhibition of p38MAPK and IL-10 expression. In addition to p38 MAPK, Rituximab also inhibited NF-kappaB activity. Inhibition of the Src PTKs, MAPK, and NF-kappaB activities by Rituximab or by specific chemical inhibitors sensitized the cells to CDDP-mediated apoptosis. The above signaling-mediated effects by Rituximab were observed with similar kinetics beginning at 1 h following treatment. Thus, altogether, these results demonstrate that signaling by Rituximab results in the inhibition of the p38MAPK pathway, which in turn inhibits the transcription of IL-10 via Sp1. Inhibition of the IL-10 autocrine/paracrine loop results in the inhibition of STAT3 activity and, consequently, inhibition of Bcl-2 expression and sensitization to drugs-apoptosis. Further, Rituximab-mediated signaling identifies several new intracellular targets in NHL that may be of potential therapeutic interest for the development of new drugs in the treatment of drug-refractory NHL tumor cells.
Vega
Mario I
MI
Department of Microbiology, Immunology, and Molecular Genetics, Jonsson Comprehensive Cancer Center, University of California, 10833 Le Conte Ave. A2-060 CHS, Los Angeles, CA 90095, USA.
Huerta-Yepaz
Sara
S
Garban
Hermes
H
Jazirehi
Ali
A
Emmanouilides
Christos
C
Bonavida
Benjamin
B
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D000069283:Rituximab; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D016753:Interleukin-10; D000069283:Rituximab; D004247:DNA; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases