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Wang et al. Genotoxic NF-kB activation in cancer

NF-kB activation by directing USP10-MCPIP1 complex mutations in the gene encoding NEMO show defects
to polyubiquitinated TRAF6. [121] in B-lymphocyte differentiation. Several mutations
in NEMO map to the C-terminal ZF area that is vital
Inhibiting genotoxic NF-kB activation by for DNA damage-induced NF-kB activation. All tested
targeting PARP-1 NEMO ZF alleles have proven specifically defective
In cells undergoing apoptosis upon severe DNA for the genotoxic NF-kB pathway, although NF-kB
damage, PARP-1 is cleaved by caspases which likely activation by LPS stimulation remains largely intact. A
restrict any further activation of NF-kB. The PARP-1 prominent feature of B lymphocytes from patients with
cleavage not only diminishes the DNA repair capacity NEMO ZF mutations is the inability to carry out class
of the cells, but also blocks anti-apoptotic NF-kB switch recombination and almost complete absence of
activation in response to DNA damage, which ensures memory B cells. [130,131] Notably, microarray examination
the elimination of cells with unrepairable DNA lesions. indicated that those genes required for class switch
In signaling pathways leading to NF-kB activation, recombination and proliferation failed to be induced in
PARP-1 plays a unique role in mediating DNA damage- patient B cells undergoing class switching in vitro. [131]
induced signaling cascade. DNA damage-induced This phenotype may be explained, to some degree,
NF-kB activation is believed to play important roles in by the modest defects in CD40 signaling that are
mediating acquired resistance in cancer cells treated also observed in these samples. However, it is also
with genotoxic agents. [122,123] As NF-kB also has critical speculated that the defect in B-cell functions observed
physiological functions, selective inhibition of NF- in patients with NEMO ZF mutations may specifically
kB activated by genotoxic treatments is expected to [132]
effectively reduce therapeutic resistance to radiation require DNA damage-induced NF-kB activation.
and chemotherapies with minimal toxicity. Targeting Constitutive ATM-NEMO-NF-kB activity in AML
PARP-1 may provide an attractive opportunity for
selectively inhibiting genotoxic NF-kB activation and MDS
while sparing the canonical and alternative NF-kB Besides DNA damage-induced ATM-NEMO-
pathways. [124] dependent NF-kB activation, a recent study showed
that ATM-NEMO-NF-kB signaling is constitutively

PHYSIOLOGICAL AND PATHOLOGICAL activated in certain acute myeloid leukemia (AML)
cell lines and in a high percentage of primary
FUNCTIONS OF GENOTOXIC NF-kB myelodysplastic syndrome (MDS) and AML patient
ACTIVATION samples. [133] Utilizing the P39 AML cell line, it was
found that ATM is constitutively active with NEMO
DNA damage-induced NF-kB activation and and PIDD in the nucleus, and an ATM-NEMO nuclear
B-cell differentiation complex is clearly detectable without genotoxic
Endogenous DSBs occurrence is an obligate treatments. Inhibition of ATM by KU55933 or ATM
consequence of B-lymphocyte development because knockdown results in the loss of nuclear NEMO and
of somatic rearrangement of immunoglobulin loci that PIDD, dissociation of ATM-NEMO complex, restraint
is important for generation of antibody diversity and
isotype class switching. These physiological DSBs of NF-kB activation, and induction of cell death. Also,
+
mobilize the DDR machinery in a way reminiscent of active ATM was detected in CD34 bone marrow
the cell reaction to exogenous DNA damage. [125] As a mononuclear cells acquired from all high-risk MDS
result, mice deficient in DDR components, particularly or AML patient samples, indicating constitutive ATM
in genes required for detecting and repair of DSBs (e.g. activation. In line with this notion, pharmacological
ATM), demonstrate defects in normal B-lymphocyte inhibition of ATM induced cytoplasmic redistribution of
function and reactions to pathogens. [126] Also, in human, NEMO and PIDD (which were found constitutively in
a number of essential immune deficiencies occur, the nucleus of these cells), inhibition of constitutive NF-
owing to monogenic defects in DDR signaling. [127,128] kB activation and cell death. [133] Although constitutive
Interestingly, NF-kB activation by endogenous activation of NF-kB is frequently found in various
DSBs formed during lymphocyte differentiation has types of tumor specimens, [134-136] in many cases, the
been detected in mice. [129] Similar to the response to mechanisms that maintain NF-kB activity are unclear.
exogenous DSBs, NF-kB activation by endogenous Considering the genomic instability as a hallmark for
DSBs requires NEMO and ATM signaling. In this human cancers, [137] it is tempting to speculate that
scenario, NF-kB activation by endogenous DSBs up- endogenous DNA damage-induced signaling may
regulates a cohort of genes including Pim2 and CD40, account for, at least in part, maintaining constitutive
whose expression is required for preventing apoptosis NF-kB activation in various human malignancies, in
and B-cell development. Consistently, patients with addition to high-risk MDS and AML.
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ March 27, 2017 53