Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo 79106, TX, USA.
Oncogene. 2013 Aug 22;32(34):3980-91. doi: 10.1038/onc.2012.413. Epub 2012 Sep 17.
Deguelin is known to suppress the growth of cancer cells; however, its anti-metastatic effects have not been studied so far in any cancer model. In the present study, we aimed to evaluate the anti-metastatic potential of deguelin in vivo and in tumor growth factor-β1 (TGFβ1)-stimulated cells. Our results demonstrate that tumor growth, peritoneal dissemination and liver/lung metastasis of orthotopically implanted PanC-1-luc cells were significantly reduced in deguelin-treated mice along with the induction of apoptosis. Furthermore, deguelin-treated tumors showed increased epithelial signature such as increased expression of E-Cadherin and cytokeratin-18 and decreased expression of Snail. Similar observations were made when PanC-1, COLO-357 and L3.6pl cells were treated in vitro with deguelin. Moreover, E-cadherin was transcriptionally upregulated and accumulated in the membrane fraction of deguelin-treated cells, as indicated by increased interaction of E-Cadherin with β-catenin. TGFβ1-induced downregulation of E-Cadherin and upregulation of Snail were abrogated by deguelin treatment. In addition, deguelin inhibited TGFβ1-induced Smad3 phosphorylation and Smad4 nuclear translocation in PanC-1 cells. Furthermore, when TGFβ1-induced nuclear factor kappa B (NFκB) activation was inhibited, TGFβ1-induced Snail upregulation or E-Cadherin downregulation was blocked. Deguelin also significantly downregulated the constitutive phosphorylation and DNA binding of NFκB in a dose-dependent manner. Interestingly, overexpression of either NFκB or Snail completely abrogated deguelin-mediated epithelial-to-mesenchymal transition (EMT) inhibition, whereas overexpression of NFκB but not Snail rescued cells from deguelin-induced apoptosis. Hence, deguelin targets NFκB to induce reversal of EMT and apoptosis but downstream effectors might be different for both processes. Taken together, our results suggest that deguelin suppresses both pancreatic tumor growth and metastasis by inducing apoptosis and inhibiting EMT.
格尔德霉素已被证实能抑制癌细胞的生长；然而，迄今为止，在任何癌症模型中都没有研究过其抗转移作用。在本研究中，我们旨在评估格尔德霉素在体内和肿瘤生长因子-β1（TGFβ1）刺激的细胞中的抗转移潜能。我们的结果表明，格尔德霉素处理的小鼠的原位植入 PanC-1-luc 细胞的肿瘤生长、腹膜扩散和肝/肺转移明显减少，同时诱导了细胞凋亡。此外，格尔德霉素处理的肿瘤表现出增加的上皮特征，如 E-钙黏蛋白和细胞角蛋白-18 的表达增加，以及 SNAI1 的表达减少。当 PanC-1、COLO-357 和 L3.6pl 细胞在体外用格尔德霉素处理时，也观察到类似的现象。此外，E-钙黏蛋白的转录上调并在格尔德霉素处理细胞的膜部分积累，这表明 E-钙黏蛋白与β-连环蛋白的相互作用增加。格尔德霉素处理可阻断 TGFβ1 诱导的 E-钙黏蛋白下调和 SNAI1 上调。此外，格尔德霉素抑制 TGFβ1 诱导的 PanC-1 细胞中 Smad3 磷酸化和 Smad4 核易位。此外，当抑制 TGFβ1 诱导的核因子 kappa B（NFκB）激活时，TGFβ1 诱导的 SNAI1 上调或 E-钙黏蛋白下调被阻断。格尔德霉素还以剂量依赖性方式显著下调 NFκB 的组成性磷酸化和 DNA 结合。有趣的是，NFκB 或 SNAI1 的过表达完全消除了格尔德霉素介导的上皮-间充质转化（EMT）抑制，而 NFκB 的过表达但不是 SNAI1 的过表达挽救了细胞免受格尔德霉素诱导的细胞凋亡。因此，格尔德霉素以 NFκB 为靶点，诱导 EMT 和细胞凋亡的逆转，但这两个过程的下游效应物可能不同。总之，我们的结果表明，格尔德霉素通过诱导细胞凋亡和抑制 EMT 来抑制胰腺肿瘤的生长和转移。
