Abstract 3705: Deguelin suppresses epithelial to mesenchymal transition (EMT) in pancreatic cancer cells by Snail repression and RKIP induction: Pivotal role of NF-kB

Abstract

Abstract Metastatic disease is a primary cause of death for most cancer patients and is associated with the loss of epithelial features and the acquisition of mesenchymal characteristics, a process known as epithelial to mesenchymal transition (EMT). Hence, targeting EMT would be a novel therapeutic modality in cancer prevention. Previous reports have shown that deguelin, a derivative of rotenone induces apoptosis in cancer cells by inhibiting AKT but its potential as anti-metastatic agent remained elusive. In the present study we investigated the anti-metastatic (EMT) properties of deguelin in PanC-1 and MIA PaCa-2 pancreatic cancer cells. Our results show that deguelin significantly (P<0.0001) suppressed the migration of PanC-1 and MIA PaCa-2 cells in a wound healing assay. Further, deguelin treated PanC-1 and MIA PaCa-2 cells show reduced expression of E-cadherin and cytokeratin 18, the markers of epithelial cell phenotype. On the other hand, the expression of mesenchymal markers N-cadherin and vimentin were up regulated by degulin treatment in both the cell lines. Furthermore, deguelin significantly reduced the expression of Snail, a known EMT inducer, and increased the expression of RKIP, a tumor suppressor gene in both the cell lines. Since NF-kB hyperactivation is associated with tumor metastasis via regulation of EMT, we evaluated whether deguelin inhibit the phosphorylation of NF-kB in PanC-1 and MIA PaCa-2 cells. Our results show that deguelin significantly suppressed the constitutive phosphorylation of NF-kB at Ser-536. Inhibition of NF-kB activation by deguelin was further confirmed by DNA binding activity and EMSA. IL-1β has been shown to activate NF-κB and its transcriptional target Snail leading to increase in the expression of E-cadherin. Treatment of PanC-1 cells with IL-1β significantly attenuated deguelin induced E-cadherin repression and N-cadherin induction, indicating the involvement of NF-kB in deguelin mediated anti-metastatic activity. Ectopic expression of either Snail or NF-kB completely abolished EMT protection offered by deguelin in PanC-1 cells confirming the role of NF-kB and Snail in deguelin induced EMT inhibition. Taken together our results provide convincing evidence on the anti-metastsis properties of deguelin in pancreatic cancer. [Supported in part by R01 grants CA106953 and CA129038 (to S.K.S) awarded by the National Cancer Institute]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3705. doi:10.1158/1538-7445.AM2011-3705