Wojciechowski Wojciech, Li Huifen, Marshall Shannon, Dell'Agnola Chiara, Espinoza-Delgado Igor
Section of Hematology-Oncology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
J Immunol. 2005 Jun 15;174(12):7859-68. doi: 10.4049/jimmunol.174.12.7859.
Rituximab, a chimeric Ab directed against CD20, induces apoptosis in targeted cells. Although the majority of B cell malignancies express the CD20 Ag, only approximately 50% of patients will respond to single-agent rituximab. The available data suggest that a decreased CD20 expression could account for the lack of response observed in some patients treated with rituximab. Despite the potential critical role of CD20 in the biology of B cell malignancies, the mechanisms controlling its expression are poorly understood. We evaluated the effect of the immune modulator agent bryostatin-1 on the expression of CD20 in non-Hodgkin's lymphoma cells. Using the B cell lines, DB and RAMOS, as well as tumor cells derived from a chronic lymphocytic leukemia patient, we demonstrated that bryostatin-1 enhanced the expression of both CD20 mRNA and protein. The enhanced expression of CD20 was associated with increased transcriptional activity of the CD20 gene, whereas the stability of CD20 mRNA was not affected. The effect of bryostatin-1 on CD20 expression in non-Hodgkin's lymphoma cells was mediated through the MAPK kinase/ERK signal transduction pathway and involved protein kinase C, but was independent of p38 MAPK and was insensitive to dexamethasone. Cells pretreated with bryostatin-1 were more susceptible to the proapoptotic effect of anti-CD20 Ab. Overall, these data demonstrate for the first time that ERK phosphorylation is required for the up-regulated expression of CD20 on B cell malignancies. The findings also suggest that bryostatin-1 and rituximab could be a valuable combined therapy for B cell malignancies.
利妥昔单抗是一种针对CD20的嵌合抗体，可诱导靶细胞凋亡。尽管大多数B细胞恶性肿瘤表达CD20抗原，但只有约50%的患者对单药利妥昔单抗有反应。现有数据表明，CD20表达降低可能是部分接受利妥昔单抗治疗的患者无反应的原因。尽管CD20在B细胞恶性肿瘤生物学中可能起关键作用，但其表达调控机制却知之甚少。我们评估了免疫调节剂苔藓抑素-1对非霍奇金淋巴瘤细胞中CD20表达的影响。利用B细胞系DB和RAMOS以及一名慢性淋巴细胞白血病患者的肿瘤细胞，我们证明苔藓抑素-1可增强CD20 mRNA和蛋白的表达。CD20表达增强与CD20基因转录活性增加有关，而CD20 mRNA的稳定性未受影响。苔藓抑素-1对非霍奇金淋巴瘤细胞中CD20表达的影响是通过丝裂原活化蛋白激酶激酶/细胞外信号调节激酶（MAPK激酶/ERK）信号转导途径介导的，涉及蛋白激酶C，但不依赖p38 MAPK，且对地塞米松不敏感。用苔藓抑素-1预处理的细胞对抗CD20抗体的促凋亡作用更敏感。总体而言，这些数据首次证明ERK磷酸化是B细胞恶性肿瘤中CD20表达上调所必需的。这些发现还表明，苔藓抑素-1和利妥昔单抗可能是治疗B细胞恶性肿瘤的一种有价值的联合疗法。
