Colorectal cancer
Breast cancer
Ovarian Tumor
Lung cancer
Prostate Tumor
2007/9-28/32
Breast
Cancer Res Treat. 2007 Jul 26; [Epub ahead of print] Departments of Biochemistry
and Cancer Studies, Cancer Biomarkers and Prevention Group, Biocentre, University of Leicester, Leicester, LE1 7RH,
UK, em9@le.ac.uk. Indole-3-carbinol (I3C), a
dietary chemopreventive compound, induces cell
death in human breast cancer cells by modulating activities of Src and epidermal growth factor receptor (EGFR). The
effect of I3C on NF-kappaB, constitutively
activated in breast cancer cells, was investigated. Nuclear extracts of
MDA-MB-468, MDA-MB-231 and HBL100 cells contained all of the Rel proteins with similar expression patterns in the latter
two. The level of NF-kappaB-regulated reporter
gene expression was in the order HBL100 << MDA-MB-468 <<
MDA-MB-231. Upstream inhibition, using PI3K, EGFR or IKKbeta
inhibitors, resulted in cell-specific effects on expression of the NF-kappaB-regulated reporter gene and endogenous genes Bcl-xL, IkappaBalpha and
IL-6, as well as on cell viability. The expression patterns of Rel and several NF-kappaB-regulated
genes and the response to LY249002 in MDA-MB-468 cells contrasted with
those in other cells. I3C induced NF-kappaB-regulated
reporter gene expression at 12 h in MDA-MB-468 cells. Conversely, it was
reduced at 24 h in HBL100 cells. I3C treatment for 6 h alone or in
combination with TNFalpha induced NF-kappaB-regulated reporter gene expression, detected 5 h
later, in MDA-MB-468, but not HBL100 cells. I3C induced NF-kappaB p65/p50 DNA binding at 6.5 h, preceded
by association of IKKbeta with the Src/EGFR complex and increased phospho-IkappaBalpha
in MDA-MB468 cells. TNFalpha increased
I3C-induced apoptosis in MDA-MB-468 and MDA-MB-231 cells. It also induced
apoptosis, enhanced by I3C, in HBL100 cells. Hence, regulation of
constitutive NF-kappaB was cell-specific. I3C
influenced the NF-kappaB pathway in a
cell-specific manner, which was not related to apoptosis. However, the
combination of I3C and TNFalpha increased
apoptosis in all cell lines. PMID: 17653853 [PubMed
- as supplied by publisher]Mol
Cancer Ther. 2007 Jul;6(7):1973-82. Singh
S, Shi
Q, Bailey
ST, Palczewski MJ, Pardee AB, Iglehart JD, Biswas DK. Department
of Cancer Biology, Dana-Farber Cancer Institute, Smith Room 1058, Nuclear factor-kappaB (NF-kappaB), a
transcription factor with pleotropic effects, is
a downstream mediator of growth signaling in estrogen receptor
(ER)-negative and erbB family particularly erbB2
(HER-2/neu) receptor-positive cancer. We previously reported activation of
NF-kappaB in ER-negative breast cancer cells and
breast tumor specimens, but the consequence of inhibiting NF-kappaB activation in this subclass of breast cancer has
not been shown. In this study, we investigated the role of NF-kappaB activation by studying the tumorigenic
potential of cells expressing genetically manipulated, inducible,
dominant-negative inhibitory kappaB kinase (IKK) beta in xenograft
tumor model. Conditional inhibition of NF-kappaB
activation by the inducible expression of dominant-negative IKKbeta simultaneously blocked cell proliferation,
reinstated apoptosis, and dramatically blocked xenograft
tumor formation. Secondly, the humanized anti-erbB2 antibody trastuzumab (Herceptin) and
the specific IKK inhibitor NF-kappaB essential
modifier-binding domain peptide both blocked NF-kappaB
activation and cell proliferation and reinstated apoptosis in two
ER-negative and erbB2-positive human breast cancer cell lines that are used
as representative model systems. Combinations of these two target-specific
inhibitors synergistically blocked cell proliferation at concentrations
that were singly ineffective. Inhibition of NF-kappaB
activation with two other low molecular weight compounds, PS1145 and PS341,
which inhibited IKK activity and proteasome-mediated
phosphorylated inhibitory kappaB
protein degradation, respectively, blocked erbB2-mediated cell growth and
reversed antiapoptotic machinery. These results
implicate NF-kappaB activation in the tumorigenesis and progression of ER-negative breast
cancer. It is postulated that this transcription factor and its activation
cascade offer therapeutic targets for erbB2-positive and ER-negative breast
cancer. Functional Diversity of Flavonoids in the
Inhibition of the Proinflammatory NF-{kappa}B,
IRF, and Akt Signaling Pathways in Murine Intestinal Epithelial Cells. Halofuginone induces matrix metalloproteinases
in rat hepatic stellate cells via activation of
p38 and NFKB.
Indole-3-carbinol-induced modulation of NF-kappaB signalling is breast
cancer cell-specific and does not correlate with cell death.
Nuclear factor-kappaB
activation: a molecular therapeutic target for estrogen receptor-negative
and epidermal growth factor receptor family receptor-positive human breast
cancer.
Ruiz PA, Haller D.
Else Kroener-Fresenius-Centre for Experimental
Nutritional Medicine,
The molecular understanding of nutritional factors in the process of host
factor-mediated activation of the intestinal epithelium may play an
important role in the assessment of adjunct nutritional therapy for chronic
intestinal inflammation. We characterized the molecular mechanisms of flavonoids including apigenin,
luteolin, genistein,
3'-hydroxy-flavone, and flavone in inhibiting tumor
necrosis factor-alpha (TNF)-induced interferon-induced protein (IP)-10 gene
expression in the murine intestinal epithelial
cell (IEC) line Mode-K. We demonstrated that 3'-hydroxy-flavone but not the
chemical core structure flavone blocked
TNF-alpha-induced nuclear factor (NF)-kappaB
transcriptional activity and IP-10 expression at the level of NF-kappaB/IkappaBalpha phosphorylation/degradation
by inhibiting IkappaB kinase
activity. Although 3'-hydroxy-flavone effectively triggered p38 mitogen-activated protein kinase
signaling and late caspase-3 cleavage, the induction of apoptotic cell
death in TNF-activated IEC was not the primary mechanism inhibiting NF-kappaB transcriptional activity and IP-10 expression.
In addition to the compound-specific inhibition of TNF-induced NF-kappaB DNA binding and NF-kappaB
transcriptional activity, apigenin and luteolin selectively blocked Akt
phosphorylation/activity. The ability of these polyphenolic compounds to target various signal
transduction pathways was further supported by the observation that luteolin and 3'-hydroxy-flavone selectively induced
interferon regulatory factor (IRF)-1 degradation. Finally, we showed that genistein blocked IP-10 but not IL-6 expression through
NF-kappaB, IRF, and Akt
independent mechanisms, demonstrating the functional diversity of flavonoids in inhibiting proinflammatory
processes in IEC. In conclusion, we provide molecular evidence for the
presence of characteristic inhibition patterns of these polyphenolic
compounds to inhibit proinflammatory gene
expression in IEC through the specific modulation of the NF-kappaB, IRF and Akt signaling
pathways.
PMID: 16484540 [PubMed - in process]
Popov
Y, Patsenker
E, Bauer M, Niedobitek
E, Schulze-Krebs A,
Schuppan
D.
Division of Gastroenterology and Hepatology,
The semisynthetic plant alkaloid Halofuginone (HAL) was reported to prevent and partly
reverse experimental liver fibrosis. However, its mechanisms of action are
poorly understood. We therefore aimed to determine the antifibrotic
potential of HAL and to characterize involved signal transduction pathways
in hepatic stellate cells (HSC). Results were
compared to its in vivo effects in a rat model of reversal of established
liver fibrosis induced by thioacetamide. In vitro
HAL inhibited HSC proliferation and migration dose-dependently at submicromolar concentrations. 200nM
of HAL up-regulated matrix metalloproteinase (MMP)-3 and MMP-13 expression
between 10-50-fold, resulting in a 2-3-fold increase of interstitial collagenase activity. Procollagen
alpha1(I) and MMP-2 transcript levels were
suppressed 2-3 fold, while expression of other profibrogenic
mRNAs remained unaffected. p38 mitogen-activated
protein kinase (p38 MAPK) and nuclear factor
kappa B (NFkB) pathways were activated by HAL,
and specific inhibitors of p38 MAPK and NFkB
dose-dependently inhibited MMP-13 induction. Treatment with HAL did not
affect HSC viability and observed effects were reversible after its
removal. In vivo HAL up-regulated MMP-3 and -13 mRNA expression 1.5- and
2-fold, respectively, in cirrhotic rats, while tissue inhibitor of
metalloproteinase-1 (TIMP-1) was suppressed by 50%. In conclusion, submicromolar concentrations of HAL inhibit HSC
proliferation and migration, and upregulate their
expression of fibrolytic MMP-3 and -13 via
activation of p38 MAPK and NFkB. The remarkable
induction of MMP-3 and -13 make HAL a promising agent for antifibrotic combination therapies.
]