Abstract
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-κB activity. Inhibition of the Src PTKs, MAPK, and NF-κB 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.
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Acknowledgements
We extend our gratitude to Dr Otoniel Martinez-Maza for valuable input and support. We also thank Kate Dinh for the preparation of this manuscript. This work was supported in part by grants from Genentech, Fogarty International Center Fellowship (S.H., H.G. D43 TW00013-14), and the Jonsson Comprehensive Cancer Center at UCLA (M.V., A.J.).
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Vega, M., Huerta-Yepaz, S., Garban, H. et al. Rituximab inhibits p38 MAPK activity in 2F7 B NHL and decreases IL-10 transcription: Pivotal role of p38 MAPK in drug resistance. Oncogene 23, 3530–3540 (2004). https://doi.org/10.1038/sj.onc.1207336
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DOI: https://doi.org/10.1038/sj.onc.1207336
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