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.