title: Deguelin suppresses pancreatic tumor growth and metastasis by inhibiting epithelial-to-mesenchymal transition in an orthotopic model.
abstract: 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.
authors.affiliation: Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo 79106, TX, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Boreddy
authors.forename: S K
authors.initials: SK
authors.lastname: Srivastava
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008957:Models, Genetic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012402:Rotenone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D015820:Cadherins; D016328:NF-kappa B; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D012402:Rotenone; D008156:Luciferases; C107676:deguelin