NF-kappaB inhibition in human hepatocellular carcinoma and its potential as adjunct to sorafenib based therapy.
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.
Wu
Jian-Min
JM
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.
Sheng
Hongmiao
H
Department of Surgery, Indiana University School of Medicine, 1001 W. 10th St., OPW Rm 324A, Indianapolis, IN 46202, United States.
Saxena
Romil
R
Clarian Pathology Laboratory, Indiana University School of Medicine, Indianapolis, IN, United States.
Skill
Nicholas James
NJ
Department of Surgery, Indiana University School of Medicine, 1001 W. 10th St., OPW Rm 324A, Indianapolis, IN 46202, United States.
Bhat-Nakshatri
Poornima
P
Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, United States.
Yu
Menggang
M
Division of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, United States.
Nakshatri
Harikrishna
H
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.
Maluccio
Mary A
MA
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.
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
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