title: Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer.
abstract: NF-κB has an essential role in the initiation and progression of pancreatic cancer and specifically mediates the induction of epithelial-mesenchymal transition and invasiveness. In this study, we demonstrate the importance of activated NF-κB signaling in EMT induction, lymphovascular metastasis, and neural invasion. Modulation of NF-κB activity was accomplished through the specific NF-κB inhibitor (BAY 11-7085), triptolide, and Minnelide treatment, as well as overexpression of IKBα repressor and IKK activator plasmids. In the classical lymphovascular metastatic cascade, inhibition of NF-κB decreased the expression of several EMT transcription factors (SNAI1, SNAI2, and ZEB1) and mesenchymal markers (VIM and CDH2) and decreased in vitro invasion, which was rescued by IKK activation. This was further demonstrated in vivo via BAY 11-7085 treatment in a orthotopic model of pancreatic cancer. In vivo NF-κB inhibition decreased tumor volume; decreased tumor EMT gene expression, while restoring cell-cell junctions; and decreasing overall metastasis. Furthermore, we demonstrate the importance of active NF-κB signaling in neural invasion. Triptolide treatment inhibits Nerve Growth Factor (NGF) mediated, neural-tumor co-culture in vitro invasion, and dorsal root ganglia (DRG) neural outgrowth through a disruption in tumor-neural cross talk. In vivo, Minnelide treatment decreased neurotrophin expression, nerve density, and sciatic nerve invasion. Taken together, this study demonstrates the importance of NF-κB signaling in the progression of pancreatic cancer through the modulation of EMT induction, lymphovascular invasion, and neural invasion.
authors: Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.|Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors: Alice
authors: A
authors: Nomura
authors: Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors: Kaustav
authors: K
authors: Majumder
authors: Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.|Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors: Bhuwan
authors: B
authors: Giri
authors: Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.|Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA.
authors: Patricia
authors: P
authors: Dauer
authors: Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.|Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors: Vikas
authors: V
authors: Dudeja
authors: Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.|Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors: Sabita
authors: S
authors: Roy
authors: Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.|Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors: Sulagna
authors: S
authors: Banerjee
authors: Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.|Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors: Ashok K
authors: AK
authors: Saluja
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008819:Mice, Nude; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology; D009368:Neoplasm Transplantation; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010525:Peripheral Nerves / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010524:Peripheral Nervous System Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control / Q000556:secondary*; D011994:Recombinant Proteins / Q000378:metabolism; D012584:Sciatic Nerve / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D011994:Recombinant Proteins; D000072000:NF-KappaB Inhibitor alpha