Deguelin Suppresses Pancreatic Tumor Growth and Metastasis by Inhibiting Epithelial to Mesenchymal Transition in an Orthotopic Model()

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 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 up-regulated and accumulated in the membrane fraction of deguelin-treated cells as indicated by increased interaction of E-Cadherin with β-catenin. TGFβ1-induced down-regulation of E-Cadherin and up-regulation 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 NFkB activation was inhibited, TGFβ1-induced Snail up-regulation or E-Cadherin down-regulation was blocked. Deguelin also significantly down regulated the constitutive phosphorylation and DNA binding of NFkB in a dose dependent manner. Interestingly, overexpression of either NFkB or Snail completely abrogated deguelin-mediated EMT inhibition, whereas overexpression of NFkB but not Snail rescued cells from deguelin-induced apoptosis. Hence, deguelin targets NFkB 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 epithelial to mesenchymal transition.