Abstract
Nuclear factor-kappaB (NF-κB) has been shown to play an important role in the development and progression of cancer. In this study, we systematically examined NF-κBp65 signaling pathway in both human hepatocellular carcinoma (HCC) tissue and HCC cell lines. NF-κBp65 signaling pathway is aberrantly expressed and activated in both human HCC tissue and HCC Hep3B cells. Inhibition of NF-κB 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-κB activity strongly sensitized Hep3B cells to sorafenib-induced cell death. Mechanistically, combined treatment of sorafenib and NF-κB inhibition enhanced inhibition of MAPK signaling and down-regulation of anti-apoptotic protein Mcl-1 expression. These observations indicate that inhibition of NF-κB may be a potential antineoplastic therapy for HCC, especially the combination of NF-κB inhibition and sorafenib provides a novel therapeutic strategy for patients with advanced-stage HCC.
| Original language | English |
|---|---|
| Pages (from-to) | 145-155 |
| Number of pages | 11 |
| Journal | Cancer Letters |
| Volume | 278 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jun 18 2009 |
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Keywords
- Hepatocellular carcinoma (HCC)
- NF-κB
- Sorafenib
- Therapy
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
NF-κB inhibition in human hepatocellular carcinoma and its potential as adjunct to sorafenib based therapy. / Wu, Jian Min; Sheng, Hongmiao; Saxena, Romil; Skill, N.; Bhat-Nakshatri, Poornima; Yu, Menggang; Nakshatri, Harikrishna; Maluccio, Mary.
In: Cancer Letters, Vol. 278, No. 2, 18.06.2009, p. 145-155.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - NF-κB inhibition in human hepatocellular carcinoma and its potential as adjunct to sorafenib based therapy
AU - Wu, Jian Min
AU - Sheng, Hongmiao
AU - Saxena, Romil
AU - Skill, N.
AU - Bhat-Nakshatri, Poornima
AU - Yu, Menggang
AU - Nakshatri, Harikrishna
AU - Maluccio, Mary
PY - 2009/6/18
Y1 - 2009/6/18
N2 - Nuclear factor-kappaB (NF-κB) has been shown to play an important role in the development and progression of cancer. In this study, we systematically examined NF-κBp65 signaling pathway in both human hepatocellular carcinoma (HCC) tissue and HCC cell lines. NF-κBp65 signaling pathway is aberrantly expressed and activated in both human HCC tissue and HCC Hep3B cells. Inhibition of NF-κB 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-κB activity strongly sensitized Hep3B cells to sorafenib-induced cell death. Mechanistically, combined treatment of sorafenib and NF-κB inhibition enhanced inhibition of MAPK signaling and down-regulation of anti-apoptotic protein Mcl-1 expression. These observations indicate that inhibition of NF-κB may be a potential antineoplastic therapy for HCC, especially the combination of NF-κB inhibition and sorafenib provides a novel therapeutic strategy for patients with advanced-stage HCC.
AB - Nuclear factor-kappaB (NF-κB) has been shown to play an important role in the development and progression of cancer. In this study, we systematically examined NF-κBp65 signaling pathway in both human hepatocellular carcinoma (HCC) tissue and HCC cell lines. NF-κBp65 signaling pathway is aberrantly expressed and activated in both human HCC tissue and HCC Hep3B cells. Inhibition of NF-κB 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-κB activity strongly sensitized Hep3B cells to sorafenib-induced cell death. Mechanistically, combined treatment of sorafenib and NF-κB inhibition enhanced inhibition of MAPK signaling and down-regulation of anti-apoptotic protein Mcl-1 expression. These observations indicate that inhibition of NF-κB may be a potential antineoplastic therapy for HCC, especially the combination of NF-κB inhibition and sorafenib provides a novel therapeutic strategy for patients with advanced-stage HCC.
KW - Hepatocellular carcinoma (HCC)
KW - NF-κB
KW - Sorafenib
KW - Therapy
UR - http://www.scopus.com/inward/record.url?scp=64649087510&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=64649087510&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2008.12.031
DO - 10.1016/j.canlet.2008.12.031
M3 - Article
C2 - 19303700
AN - SCOPUS:64649087510
VL - 278
SP - 145
EP - 155
JO - Cancer Letters
JF - Cancer Letters
SN - 0304-3835
IS - 2
ER -