Biomedical Engineering Reference
In-Depth Information
B (see
Figure 8.4
). For example, gene profiling
has identified a subset of diffuse large B cell lymphoma that requires NF-
and processes controlled by NF-
κ
κ
B for
growth and survival. Inhibition of NF-
B activation blocks the expression of key
genes associated with this type of lymphoma [118]. We have identified a set of
approximately 25 genes, which are regulated by NF-
κ
κ
B in a manner dependent on
oncogenic Ras expression in murine fibroblasts [106].
One of the key properties associated with transformed cells is their ability to
resist apoptosis. Experiments have revealed that induction of RasV12 in immortal-
ized Rat1 fibroblasts leads to cellular transformation but not to apoptosis. If NF-
κ
B
is inhibited in these cells by expression of I
-superrepressor (SR), then the
induction of RasV12 expression induces high levels of apoptosis [119]. Consistent
with this point, inhibition of NF-
κ
B
α
B in certain tumor cell lines leads to apoptotic
cell death [103]. Hodgkin's lymphoma has proven to be a cancer that is strongly
controlled by NF-
κ
B activation. Proliferation and survival of Hodgkin/Reed-Stern-
berg cells is blocked when NF-
κ
κ
B is inhibited by I
κ
B
α
expression [120]. Genes
B that suppress apoptosis, such as Bcl-2 and Bcl-x
L
, are often
expressed in human cancers, and inhibition of NF-
regulated by NF-
κ
B in Hodgkin/Reed-Sternberg
cells led to the loss of expression of antiapoptotic effectors A1/Bfl-1, c-IAP2,
TRAF1, and Bcl-x
L
[121]. Relating to a role for the NF-
κ
κ
B pathway in preventing
apoptosis, Hu and colleagues [122] have shown that IKK
activation in breast cancer
cells leads to the direct phosphorylation and degradation of the proapoptotic factor
Foxo3a, suppressing apoptotic potential in certain breast cancer cells and promoting
cell proliferation. Consistent with these findings, NF-
β
B has been shown to be
activated by certain chemotherapies and radiation, and this response is generally
antiapoptotic [103]. Inhibition of NF-
κ
B in these models results in enhanced che-
motherapy-induced apoptosis [103,123,124]. However, it has been reported that
NF-
κ
B can function in some cancer cell types in a proapoptotic manner downstream
of certain chemotherapies [125]. Thus, as we have seen in inflammation and hemato-
poiesis (
Chapter 7
), NF-
κ
κ
B does not function uniformly in inhibiting apoptosis in
all cancer cells.
NF-
B activation also appears to promote cellular proliferation, which is con-
sistent with a role in promoting growth sufficiency of cancer cells. Evidence has
been presented that NF-
κ
B can bind and activate the cyclin D1 promoter, promoting
κ
B homologue Bcl-3, in
association with p52 homodimers, has also been found to potently activate transcrip-
tion of the cyclin D1 gene. Interestingly, IKK
κ
has been proposed to play a role in
cyclin D1 transcription through the Tcf site via its ability to control
α
β
-catenin
phosphorylation [126]. Consistent with a role for IKK
α
in promoting cyclin D1
transcription, Karin and colleagues found that IKK
is required for RANK signaling
and cyclin D1 expression in mammary gland development [127]. Other mechanisms
whereby NF-
α
B may potentiate oncogenic conversion and maintenance are through
the upregulation of HIF-1
κ
α
[128] and the regulation of c-myc transcription [129].
B activation in tumor cells and in tumor-associated stromal and endothelial
cells likely plays a role in tumor progression. In this regard, NF-
NF-
κ
B has been reported
to promote both angiogenesis and metastasis in certain tumor models, potentially
through regulation of VEGF and MMPs [103,104]. A role for NF-
κ
κ
B in invading
