小根蒜甾体皂苷单体 DT-13 通过调控组织因子抑制低氧下人乳腺癌细胞黏附和迁移
The saponin monomer of dwarf lilyturf tuber, DT-13, reduces human breast cancer cell adhesion and migration during hypoxia via regulation of tissue factor.
机构信息
Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, P. R. China.
出版信息
Biol Pharm Bull. 2010;33(7):1192-8. doi: 10.1248/bpb.33.1192.
Adhesion and migration of tumor cells are crucial steps in tumor invasion and metastasis. In the present study, we investigated the effects of saponin monomer 13 of dwarf lilyturf tuber (DT-13) on metastasis of human breast cancer cells (MDA-MB-435) during hypoxia. The effects and molecular mechanisms of DT-13 on MDA-MB-435 cells metastatic phenotype in vitro and in vivo were evaluated by RNA interference; quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assays. DT-13 had no significant effects on cell adhesion and migration under normoxia conditions. Under hypoxic conditions, MDA-MB-435 adhesion to vitronectin was inhibited by about 43.5% or 60.8% after exposure of the cells to DT-13 at 1 microM or 10 microM, respectively. DT-13 decreased the migratory response by hypoxia at 1 or 10 microM, and inhibition ratios were 20% and 30%, respectively. DT-13 inhibited hypoxia-induced expression of alphavbeta3 integrin, tissue factor (TF) and early growth response gene-1 (Egr-1) and decreased excretion of matrix metalloproteinase 9 (MMP-9) of MDA-MB-435 cells under hypoxic conditions. After Egr-1 short interference RNA (siRNA) treatment, DT-13 could still inhibit the up-regulation of TF mRNA and protein levels and its pro-coagulant activity (PCA) under hypoxia. In nude mice, DT-13 decreased extravasation of MDA-MB-435 cells in the lung after tail vein injection. Our data suggest that DT-13 inhibits MDA-MB-435 cells metastasis during hypoxia via regulation of TF, and the effect of DT-13 on TF is partly mediated by Egr-1.
肿瘤细胞的黏附和迁移是肿瘤侵袭和转移的关键步骤。在本研究中，我们研究了菝葜皂苷元 13（DT-13）单体在低氧条件下对人乳腺癌细胞（MDA-MB-435）转移的影响。通过 RNA 干扰、实时定量聚合酶链反应（qRT-PCR）和 Western blot 检测，评估了 DT-13 对 MDA-MB-435 细胞体外和体内转移表型的影响及其分子机制。在常氧条件下，DT-13 对细胞黏附和迁移没有显著影响。在低氧条件下，细胞暴露于 1 μM 或 10 μM 的 DT-13 后，MDA-MB-435 与玻连蛋白的黏附分别抑制约 43.5%和 60.8%。DT-13 以 1 或 10 μM 抑制低氧诱导的迁移反应，抑制率分别为 20%和 30%。DT-13 抑制低氧诱导的 MDA-MB-435 细胞整合素 αvβ3、组织因子（TF）和早期生长反应基因-1（Egr-1）表达，并减少基质金属蛋白酶 9（MMP-9）的分泌。在 Egr-1 短发夹 RNA（siRNA）处理后，DT-13 仍能抑制低氧条件下 TF mRNA 和蛋白水平及其促凝活性（PCA）的上调。在裸鼠中，DT-13 减少了尾静脉注射后 MDA-MB-435 细胞在肺部的渗出。我们的数据表明，DT-13 通过调节 TF 抑制 MDA-MB-435 细胞在低氧条件下的转移，DT-13 对 TF 的作用部分是通过 Egr-1 介导的。
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