中文摘要
NF-κB是联系炎症与肿瘤的关键核转录因子,其下游靶基因IL-6在白血病发生过程中发挥重要功能。苦参碱是中药苦参中分离出的一种生物碱,具有较为明确的抗炎抗肿瘤活性,但其是否通过NF-κB通路发挥抗肿瘤作用目前尚不清楚。我们的前期研究发现,苦参碱可显著抑制人白血病K562细胞增殖,降低其IL-6表达,同时抑制细胞内NF-κB及JAK2、STAT3的磷酸化。我们推测:苦参碱可能通过抑制NF-κB转录活性下调IL-6表达及其下游的JAK/STAT3通路活性,发挥抗白血病作用。本项目拟以苦参碱处理的白血病细胞为模型,从分子、细胞和整体动物水平确认苦参碱对NF-κB表达及转录活性作用,探讨NF-κB及其介导的IL-6/JAK/STAT3通路在苦参碱抗白血病作用中的分子机制,以期阐明苦参碱的抗白血病作用机制,为探索白血病治疗新策略提供实验依据。
英文摘要
Nuclear factor NF-κB functions as a central point linking inflammation and cancer. Its downstream targeted gene interleukin 6 (IL-6) and IL-6-mediated JAK/STAT3 signaling pathway plays an important role in leukemogenesis. Matrine is an alkaloid compound purified from Sophora flavescensm, which shows anti-inflammatory and anti-cancer acivities both in vitro and in vivo. However, the exact molecular targets or pathways contribute to its anti-cancer activities remains unclear. Our previous study found treatment with matrine could suppress the cell proliferation of human myeloid leukemia cells K562 significantly and down-regulate the expression of IL-6 in both transcriptional and protein level. Further investigations found that matrine could down-regulate the phosphorylation of STAT3 and JAK2 as well as that of nuclear factor κB(NF-κB). Based on these,findings, it is speculated that the anti-leukemia effects of matrine might be mediated via its regulating the activities of NF-κB signaling cohort in leukemia cells. In the present study, we aim to further validate the exact role of matrine in regulating the activities of NF-κB/IL-6 signaling cohort in molecular, cellular and mice model levels by using a matrine-treated leukimia cells model based studies. The findings in this study would decipher the molecular mechanisms via which matrine exert its anti-leukemia effect and shed some light on building novel strategies for treatment of leukemia.
