Vega Mario I, Huerta-Yepaz Sara, Garban Hermes, Jazirehi Ali, Emmanouilides Christos, Bonavida Benjamin
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.
Oncogene. 2004 Apr 29;23(20):3530-40. doi: 10.1038/sj.onc.1207336.
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.
我们最近报道，利妥昔单抗（抗CD20）通过下调IL-10和Bcl-2表达，使耐药的2F7和10C9 B非霍奇金淋巴瘤（NHL）细胞系对各种化疗药物的凋亡作用敏感。研究了利妥昔单抗诱导IL-10下调的机制。我们假设利妥昔单抗可能抑制通过Sp1调节IL-10表达的p38 MAPK活性。用利妥昔单抗或p38抑制剂SB203580处理2F7细胞可抑制组成型p38 MAPK活性，并导致Sp1、IL-10、STAT3和Bcl-2的抑制。用特异性Src家族激酶抑制剂PP2抑制p38MAPK途径的Src家族蛋白酪氨酸激酶、Lyn和Src家族蛋白酪氨酸激酶上游信号分子，导致p38MAPK和IL-10表达的抑制。除p38 MAPK外，利妥昔单抗还抑制NF-κB活性。利妥昔单抗或特异性化学抑制剂对Src蛋白酪氨酸激酶、MAPK和NF-κB活性的抑制使细胞对顺铂介导的凋亡敏感。利妥昔单抗的上述信号介导作用在处理后1小时开始以相似的动力学观察到。因此，总的来说，这些结果表明利妥昔单抗的信号传导导致p38MAPK途径的抑制，进而通过Sp1抑制IL-10的转录。IL-10自分泌/旁分泌环的抑制导致STAT3活性的抑制，从而抑制Bcl-2表达并使细胞对药物诱导的凋亡敏感。此外，利妥昔单抗介导的信号传导在NHL中确定了几个新的细胞内靶点，这些靶点可能对开发治疗难治性NHL肿瘤细胞的新药具有潜在的治疗意义。
