Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Cancer Prev Res (Phila). 2011 Jul;4(7):1107-17. doi: 10.1158/1940-6207.CAPR-10-0306. Epub 2011 Apr 4.
We showed previously that cruciferous vegetable constituent benzyl isothiocyanate (BITC) inhibits growth of cultured and xenografted human breast cancer cells and suppresses mammary cancer development in a transgenic mouse model. We now show, for the first time, that BITC inhibits epithelial-mesenchymal transition (EMT) in human breast cancer cells. Exposure of estrogen-independent MDA-MB-231 and estrogen-responsive MCF-7 human breast cancer cell lines and a pancreatic cancer cell line (PL-45) to BITC resulted in upregulation of epithelial markers (e.g., E-cadherin and/or occludin) with a concomitant decrease in protein levels of mesenchymal markers, including vimentin, fibronectin, snail, and/or c-Met. The BITC-mediated induction of E-cadherin protein was accompanied by an increase in its transcription, whereas BITC-treated MDA-MB-231 cells exhibited suppression of vimentin, snail, and slug mRNA levels. Experimental EMT induced by exposure to TGFβ and TNFα or Rb knockdown in a spontaneously immortalized nontumorigenic human mammary epithelial cell line (MCF-10A) was also partially reversed by BITC treatment. The TGFβ-/TNFα-induced migration of MCF-10A cells was inhibited in the presence of BITC, which was partially attenuated by RNA interference of E-cadherin. Inhibition of MDA-MB-231 xenograft growth in vivo in female athymic mice by BITC administration was associated with an increase in protein level of E-cadherin and suppression of vimentin and fibronectin protein expression. In conclusion, this study reports a novel anticancer effect of BITC involving inhibition of EMT, a process triggered during progression of cancer to invasive state.
我们之前已经证明十字花科蔬菜成分苄基异硫氰酸酯（BITC）能够抑制培养和异种移植的人类乳腺癌细胞的生长，并抑制转基因小鼠模型中的乳腺癌发展。我们现在首次表明，BITC 能够抑制人类乳腺癌细胞的上皮-间充质转化（EMT）。暴露于雌激素非依赖性 MDA-MB-231 和雌激素反应性 MCF-7 人类乳腺癌细胞系和胰腺癌细胞系（PL-45）中的 BITC 导致上皮标志物（例如 E-钙粘蛋白和/或紧密连接蛋白）的上调，同时伴随着间充质标志物（包括波形蛋白、纤维连接蛋白、蜗牛和/或 c-Met）的蛋白水平降低。BITC 介导的 E-钙粘蛋白蛋白诱导伴随着其转录的增加，而 BITC 处理的 MDA-MB-231 细胞表现出抑制波形蛋白、蜗牛和 slug mRNA 水平。通过暴露于 TGFβ 和 TNFα 或 Rb 敲低在自发永生化非致瘤性人乳腺上皮细胞系（MCF-10A）中诱导的实验性 EMT 也部分被 BITC 处理逆转。存在 BITC 时，TGFβ-/TNFα 诱导的 MCF-10A 细胞迁移受到抑制，而 E-钙粘蛋白的 RNA 干扰部分减弱了这种抑制作用。BITC 给药抑制体内雌性无胸腺小鼠 MDA-MB-231 异种移植物的生长与 E-钙粘蛋白蛋白水平的增加以及波形蛋白和纤维连接蛋白蛋白表达的抑制有关。总之，这项研究报告了 BITC 的一种新的抗癌作用，涉及 EMT 的抑制，这是癌症进展到侵袭状态时触发的一个过程。
