Therapeutic intervention of silymarin on the migration of non-small cell lung cancer cells is associated with the axis of multiple molecular targets including class 1 HDACs, ZEB1 expression, and restoration of miR-203 and E-cadherin expression.
Therapeutic intervention of silymarin on the migration of non-small cell lung cancer cells is associated with the axis of multiple molecular targets including class 1 HDACs, ZEB1 expression, and restoration of miR-203 and E-cadherin expression.
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发表时间：
2016-06
影响因子：
5.3
通讯作者：
T. Singh;R. Prasad;S. Katiyar
中科院分区：
文献类型：
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作者：
T. Singh;R. Prasad;S. Katiyar
肺癌及其转移是世界范围内癌症相关死亡的主要原因。非小细胞肺癌（NSCLC）占肺癌总病例的约90%。尽管治疗方法取得了进展，但仅取得了有限的改善。因此，需要替代策略来管理肺癌。本文报道了水飞蓟素的化疗作用。Gaertn.），使用转移性人NSCLC细胞系（A549、H1299和H460）以及这些效应背后的分子靶点对NSCLC细胞迁移的影响。使用体外细胞迁移试验，我们发现人NSCLC细胞的治疗（A549、H1299和H460）与水飞蓟素（0、5、10和20 μg/mL）24 h导致细胞迁移的浓度依赖性抑制，这与组蛋白脱乙酰酶（HDAC）活性的抑制和1类HDAC蛋白水平的降低有关HDAC 1、HDAC 2、HDAC 3和HDAC 8）以及伴随的组蛋白乙酰转移酶活性（HAT）水平的增加。已知的HDAC抑制剂（丁酸钠和阿司他丁A）对肺癌细胞表现出相似的治疗效果模式。用水飞蓟素处理A549和H460细胞，降低转录因子ZEB 1的表达，恢复E-钙粘蛋白的表达。ZEB 1的siRNA敲低也降低了NSCLC细胞中HDAC蛋白的表达，并增强了E-钙粘蛋白水平的再表达。microRNA-203（miR-203）作为肿瘤抑制因子，调节肿瘤细胞侵袭，并在癌细胞中被ZEB 1抑制。水飞蓟素治疗恢复了NSCLC细胞中miR-203的水平。这些研究结果表明，水飞蓟素可以有效地抑制肺癌细胞迁移，并提供了一个连贯的模型，其作用机制表明，水飞蓟素可能是一个重要的治疗选择，用于预防或治疗肺癌转移时，无论是单独或与标准的癌症治疗药物。
Lung cancer and its metastasis is the leading cause of cancer-related mortality world-wide. Non-small cell lung cancer (NSCLC) accounts for about 90% of total lung cancer cases. Despite advancements in therapeutic approaches, only limited improvement has been achieved. Therefore, alternative strategies are required for the management of lung cancer. Here we report the chemotherapeutic effect of silymarin, a phytochemical from milk thistle plant (Silybum marianum L. Gaertn.), on NSCLC cell migration using metastatic human NSCLC cell lines (A549, H1299 and H460) together with the molecular targets underlying these effects. Using an in vitro cell migration assay, we found that treatment of human NSCLC cells (A549, H1299 and H460) with silymarin (0, 5, 10 and 20 µg/mL) for 24 h resulted in concentration-dependent inhibition of cell migration, which was associated with the inhibition of histone deacetylase (HDAC) activity and reduced levels of class 1 HDAC proteins (HDAC1, HDAC2, HDAC3 and HDAC8) and concomitant increases in the levels of histone acetyltransferase activity (HAT). Known HDAC inhibitors (sodium butyrate and trichostatin A) exhibited similar patterns of therapeutic effects on the lung cancer cells. Treatment of A549 and H460 cells with silymarin reduced the expression of the transcription factor ZEB1 and restored expression of E-cadherin. The siRNA knockdown of ZEB1 also reduced the expression of HDAC proteins and enhanced re-expression of the levels of E-cadherin in NSCLC cells. MicroRNA-203 (miR-203) acts as a tumor suppressor, regulates tumor cell invasion and is repressed by ZEB1 in cancer cells. Silymarin treatment restored the levels of miR-203 in NSCLC cells. These findings indicate that silymarin can effectively inhibit lung cancer cell migration and provide a coherent model of its mechanism of action suggesting that silymarin may be an important therapeutic option for the prevention or treatment of lung cancer metastasis when administered either alone or with standard cancer therapeutic drugs.