Deguelin suppresses pancreatic tumor growth and metastasis by inhibiting epithelial-to-mesenchymal transition in an orthotopic model
Open Access
- 17 September 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 32 (34), 3980-3991
- https://doi.org/10.1038/onc.2012.413
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.Keywords
This publication has 50 references indexed in Scilit:
- Pancreatic Ductal Adenocarcinoma Mice Lacking Mucin 1 Have a Profound Defect in Tumor Growth and MetastasisCancer Research, 2011
- Pancreatic Tumor Suppression by Benzyl Isothiocyanate Is Associated with Inhibition of PI3K/AKT/FOXO PathwayClinical Cancer Research, 2011
- Benzyl Isothiocyanate–Mediated Inhibition of Histone Deacetylase Leads to NF-κB Turnoff in Human Pancreatic Carcinoma CellsMolecular Cancer Therapeutics, 2010
- Gemcitabine Sensitivity Can Be Induced in Pancreatic Cancer Cells through Modulation of miR-200 and miR-21 Expression by Curcumin or Its Analogue CDFCancer Research, 2010
- Acquisition of Epithelial-Mesenchymal Transition Phenotype of Gemcitabine-Resistant Pancreatic Cancer Cells Is Linked with Activation of the Notch Signaling PathwayCancer Research, 2009
- The Role of STAT-3 in the Induction of Apoptosis in Pancreatic Cancer Cells by Benzyl IsothiocyanateJNCI Journal of the National Cancer Institute, 2009
- Epithelial-Mesenchymal Transition Markers in Pancreatic Ductal AdenocarcinomaPancreas, 2009
- Non-Smad pathways in TGF-β signalingCell Research, 2008
- TGF-β coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survivalExperimental Cell Research, 2008
- Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional PathwaysCancer Research, 2008