title: NF-kappaB inhibition in human hepatocellular carcinoma and its potential as adjunct to sorafenib based therapy.
abstract: Nuclear factor-kappaB (NF-kappaB) has been shown to play an important role in the development and progression of cancer. In this study, we systematically examined NF-kappaBp65 signaling pathway in both human hepatocellular carcinoma (HCC) tissue and HCC cell lines. NF-kappaBp65 signaling pathway is aberrantly expressed and activated in both human HCC tissue and HCC Hep3B cells. Inhibition of NF-kappaB activity significantly reduced proliferation and invasion of Hep3B cells as well as down-regulated the expression of invasion-related molecules including matrix metalloproteinase (MMP)-2, MMP-9, membrane type-1 MMP (MT1-MMP), urokinase plasminogen activator (uPA) and vascular endothelial growth factor (VEGF). Hep3B cells exhibited a dose-dependent increase in apoptosis after receiving sorafenib treatment. Inhibition of NF-kappaB activity strongly sensitized Hep3B cells to sorafenib-induced cell death. Mechanistically, combined treatment of sorafenib and NF-kappaB inhibition enhanced inhibition of MAPK signaling and down-regulation of anti-apoptotic protein Mcl-1 expression. These observations indicate that inhibition of NF-kappaB may be a potential antineoplastic therapy for HCC, especially the combination of NF-kappaB inhibition and sorafenib provides a novel therapeutic strategy for patients with advanced-stage HCC.
authors.affiliation: Department of Surgery, Indiana University School of Medicine, 1001 W. 10th St., OPW Rm 324A, Indianapolis, IN 46202, United States. Electronic address: jw17@iupui.edu.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Wu
authors.affiliation: Department of Surgery, Indiana University School of Medicine, 1001 W. 10th St., OPW Rm 324A, Indianapolis, IN 46202, United States.
authors.forename: Hongmiao
authors.initials: H
authors.lastname: Sheng
authors.affiliation: Clarian Pathology Laboratory, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Romil
authors.initials: R
authors.lastname: Saxena
authors.affiliation: Department of Surgery, Indiana University School of Medicine, 1001 W. 10th St., OPW Rm 324A, Indianapolis, IN 46202, United States.
authors.forename: Nicholas James
authors.initials: NJ
authors.lastname: Skill
authors.affiliation: Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Poornima
authors.initials: P
authors.lastname: Bhat-Nakshatri
authors.affiliation: Division of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Menggang
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Surgery, Indiana University School of Medicine, 1001 W. 10th St., OPW Rm 324A, Indianapolis, IN 46202, United States; Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Nakshatri
authors.affiliation: Department of Surgery, Indiana University School of Medicine, 1001 W. 10th St., OPW Rm 324A, Indianapolis, IN 46202, United States. Electronic address: mmalucci@iupui.edu.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Maluccio
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D020672:I-kappa B Proteins / Q000502:physiology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009361:Neoplasm Invasiveness; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011725:Pyridines / Q000627:therapeutic use*; D015398:Signal Transduction; D000077157:Sorafenib; D051996:Transcription Factor RelA / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D020672:I-kappa B Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D009536:Niacinamide; D000077157:Sorafenib