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Deguelin Suppresses Pancreatic Tumor Growth and Metastasis by Inhibiting Epithelial-To-Mesenchymal Transition in an Orthotopic Model

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Deguelin Suppresses Pancreatic Tumor Growth and Metastasis by Inhibiting Epithelial-To-Mesenchymal Transition in an Orthotopic Model Oncogene (2013) 32, 3980–3991 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc ORIGINAL ARTICLE Deguelin suppresses pancreatic tumor growth and metastasis by inhibiting epithelial-to-mesenchymal transition in an orthotopic model SR Boreddy and SK Srivastava 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-b1 (TGFb1)-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 b-catenin. TGFb1-induced downregulation of E-Cadherin and upregulation of Snail were abrogated by deguelin treatment. In addition, deguelin inhibited TGFb1-induced Smad3 phosphorylation and Smad4 nuclear translocation in PanC-1 cells. Furthermore, when TGFb1-induced nuclear factor kappa B (NFkB) activation was inhibited, TGFb1-induced Snail upregulation or E-Cadherin downregulation was blocked. Deguelin also significantly downregulated the constitutive phosphorylation and DNA binding of NFkB in a dose- dependent manner. Interestingly, overexpression of either NFkB or Snail completely abrogated deguelin-mediated epithelial-to- mesenchymal transition (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 EMT. Oncogene (2013) 32, 3980–3991; doi:10.1038/onc.2012.413; published online 17 September 2012 Keywords: NFkB; TGF-b; RKIP; Snail; metastasis; apoptosis INTRODUCTION canonical Smad signaling and/or non-canonical TGFb/TAK1/IKK/ Pancreatic cancer is the fourth leading cause of cancer-related NFkB signaling, but both the pathways merges on Snail to repress deaths in the United States.1 Most of the patients with pancreatic E-Cadherin expression.8 The most important suppressors of cancer develop metastasis and die because of the debilitating E-Cadherin are Snail-related zinc-finger transcription factors such metabolic effects of their unrestrained growth.2 Several well- as Snail, Slug and SIP-1/ZEB.9 Interestingly, Snail-knockout animals known factors such as late detection and resistance to chemo- die at gastrulation stages and show defects in EMT, indicating the and radiotherapy contribute to poor survival rate. Pancreatic role of Snail in EMT induction.10 Recently, nuclear factor kappa B cancer commonly metastasize to the abdominal cavity, lymph (NFkB) was identified as a central mediator of EMT by regulating nodes and liver.3 Snail expression.11,12 Huber et al.11 have shown that the activation Emerging evidences suggest that epithelial-to-mesenchymal of NFkB promoted the transition to a mesenchymal phenotype transition (EMT) is a key process in tumor cell invasiveness and even in the absence of TGFb. Moreover, inhibition of NFkBin metastasis. Previous reports have shown a close association metastatic cells resulted in reversal of EMT, suggesting that the between pancreatic cancer progression and EMT.4 In fact several IKK-2/IkBa/NFkB pathway is required for the induction and pancreatic cancer cell lines and surgically resected pancreatic maintenance of EMT in epithelial cancer cells.11 tumors have shown strong EMT characteristics.4–6 Interestingly, Recognition of EMT as a potential mechanism for metastasis increase in fibronectin or vimentin and decrease in E-Cadherin may offer new targets for therapeutic intervention.13 Such expression in tumors correlates with poor survival.5 A recent report therapeutic intervention might prevent tumor invasion and has shown that 43% (13/30) of primary pancreatic tumors and 53% block metastasis, if applied at an early phase of tumor growth. If (8/15) of metastatic tumors have increased levels of N-Cadherin, a primary tumor has already metastasized to distant sites, anti- indicating the potential role of EMT in pancreatic cancer metastasis.6 EMT approach alone may not be sufficient. Tumor growth factor-b1 (TGFb1) can induce and maintain EMT Deguelin, a rotenoid isolated from Mundulea sericea Willd. during embryogenesis and cancer progression.7 It induces EMT by (Leguminosae) has shown to be a potential anti-cancer agent in Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX, USA. Correspondence: Professor SK Srivastava, Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, 1406 Coulter, Suite 1103, ARB, Amarillo, TX 79106, USA. E-mail: [email protected] Received 9 February 2012; revised 11 July 2012; accepted 25 July 2012; published online 17 September 2012 Deguelin suppresses pancreatic tumor metastasis SR Boreddy and SK Srivastava 3981 various cancer models such as breast, colon and lung cancer.14–16 loss or signs of acute or delayed toxicity (Figure 1d). Interestingly, Intravenous injection of deguelin showed a mean residence time deguelin-treated mice developed much lesser metastatic lesions of 6.98 h and terminal half-life (t1/2) of 9.26 h. About 58% and 14% in peritoneum (Figure 2a). As shown in Figure 2b, control tumors of the deguelin was eliminated via feces and urine, respectively, migrated to an average of about 20 mm away from the pancreas, within 5 days of intragastric administration of deguelin.17 Previous whereas deguelin-treated tumors migrated around 5–6 mm, reports have shown that deguelin inhibits the survival of various indicating significant inhibition of tumor cell migration by cancer cells by targeting the key survival pathways such as AKT, deguelin (20.3 vs 6.6 mm; difference ¼ 13.7 mm, 95% CI ¼ 7–20.8, Wnt, NFkB and cell cycle proteins.14–16,18,19 However, the anti- Po0.0006). In fact, 8 out of 10 mice in treated group showed no metastatic potentials of deguelin have not been investigated in metastatic lesions whereas, in the control group, 8 out of 10 mice any cancer model. The present study was designed to elucidate demonstrated metastatic lesions (Figure 2c). Compared with the role of deguelin on EMT and metastasis in pancreatic cancer. control, deguelin-treated mice exhibited reduced migration of PanC-1 cells into various organs such as liver, lung, spleen, intestinal mesentery nodules and abdominal cavity (Figures 2c RESULTS and d, indicating that deguelin inhibits the metastasis of primary Deguelin inhibits primary tumor growth and spontaneous in vivo implanted tumors to liver and lungs. As liver is the preferential site metastasis of pancreatic tumors of metastasis for most of the pancreatic tumors, we imaged the Previous reports have shown that deguelin inhibits the growth of luminescence in liver. Luciferin was injected 10 min before killing cancer cells.16,20,21 In the present study, we evaluated whether the mice, livers were excised and luminescence was measured by deguelin could inhibit the metastasis of pancreatic cancer along the imaging system. As shown in Figure 2e, liver from deguelin- with primary tumor growth. To determine the anti-metastasis treated mice showed no or modest luminescence, whereas control potential of deguelin in vivo, mice that were orthopically mice livers demonstrated strong luminescence indicating that implanted with PanC-1-luc cells were treated with 5 mg/kg deguelin significantly inhibits the metastasis of pancreatic tumors deguelin (1:1 corn oil:dimethylsulphoxide, daily, intraperitoneal to liver. (i.p.)), and tumor growth and metastasis were monitored using IVIS Bio Imaging Station. Our results show that deguelin substantially reduced the primary tumor growth by 73% Deguelin inhibits EMT in vivo (7.6 Â 107 vs 1.8 Â 107 photons/sec; difference ¼ 5.7 Â 107 As the primary objective of the present study was to evaluate the photons/sec, 95% confidence interval (CI) ¼ 6.6 Â 107 to 12 Â 108 anti-metastatic potential of deguelin, we focused further studies photons/sec, P40.087), as compared with control tumors (Figures on metastasis. Inhibition of pancreatic tumor metastasis and 1a and b). Primary tumor weight was about 63% lesser in migration by deguelin in vivo prompted us to examine whether deguelin-treated mice, as compared with control mice (Figure 1c). the anti-metastatic effect of deguelin was due to the inhibition of Deguelin was well tolerated by the mice as depicted by no weight EMT. Interestingly, our immunofluorescence studies show that 1.0×1008 Control 1.5×1008 deguelin treatment P<0.087 07 8.0×10 Treatment started 1.0×1008 6.0×1007 4.0×1007 5.0×1007 Tumor Growth Tumor 2.0×1007 (Photons/Second) Tumor Growth Photons/Second Growth Tumor 0.0 ***** 0.0 0 5 10 15 20 25 30 35 40 45 50 Control Treated Days after tumor implantation 30 1000 Control p<0.005 Deguelin (5mg/kg) 28 800 Deguelin treatment started (63% Supression) 26 600 24 400 22 Body weight (g) Body 20 200 Pancreas weight (mg) Pancreas 18 0 0 4 8 12 16 20 24 28 32 36 40 44 Control Deguelin treated Days after tumor implantation Figure 1. Deguelin suppresses primary tumor growth of pancreatic tumors. Mice were orthotopically implanted with PanC-1-luc cells and treated with deguelin (5 mg/kg, daily, i.p.) for 37 days. (a) Tumor growth was monitored by measuring luminescence of control and deguelin- treated mice twice a week by IVIS imaging station.
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