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Wang et al. Genotoxic NF-kB activation in cancer

Genotoxic NF-kB activation in acquired cancer inflammatory cytokine IL-6 and oncogenic miR-21 in
therapeutic resistance TNBC cells, which may promote TNBC cell survival
Substantial evidence indicates that NF-kB regulates and invasion upon Dox treatment. [162] Moreover, IL-6-
oncogenesis and tumor progression. NF-kB activation dependent STAT3 activation further enhanced miR-
(i.e. nuclear localization) has been observed in a variety 181a transcription, whose upregulation suppressed
of solid tumors. [138,139] In general, NF-kB is believed to pro-apoptotic gene BAX level and reduced cancer cell
promote cancer development by contributing to all apoptosis upon chemotherapy. [163] It is plausible that
intrinsic hallmarks of cancer, including therapeutic NF-kB plays a critical role in regulating therapeutic
resistance and metastasis. [137,138] Ionizing radiation resistance and subsequent metastasis in genotoxic
and chemotherapeutic drugs such as doxorubicin, drug-treated breast cancer cells, through coordinating
5-fluorouracil and cisplatin have been found to activate expression of anti-apoptotic genes, pro-inflammatory
NF-kB signaling in various cancer cells. [140-142] The cytokines and oncogenic miRNAs. Thus, inhibiting
genotoxic agent-induced NF-kB activation has been genotoxic drug-induced NF-kB activation may serve
considered as a major mechanism through which as a promising strategy to reduce chemotherapeutic
various cancers acquire therapeutic resistance. [143] resistance and subsequent metastasis.

A number of NF-kB target genes which prevent TARGETING NF-kB TO SUPPRESS
apoptosis and promote proliferation, such as cyclin THERAPEUTIC RESISTANCE
D1, bcl-2, bcl-xL, survivin, and XIAP, were upregulated
in cancer cells upon genotoxic treatments. [144-146] A number of NF-kB blocking agents, such as IKK
Furthermore, chemotherapeutic resistance of cancer inhibitors, inhibitory peptides, antisense RNA,
cells highly correlates with their ability to metastasize, proteasome inhibitors and dietary supplements,
which indicates that genotoxic treatment may induce are currently being tested in combination with
pro-metastatic responses in refractory cancer cells. [147] chemotherapy and radiotherapy. These studies aim
to sensitize cancer cells to the tumoricidal effects of
Recent studies have suggested that DNA damage chemotherapeutic drugs and radiation by blocking NF-
response could enhance the expression of pro- kB activation, thereby preventing acquired resistance.
inflammatory cytokines, such as Interleukin-6 (IL-6) and It is noteworthy that NF-kB also plays critical roles
Interleukin-8 (IL-8), favoring tumor growth, angiogenesis in regulating physiological process, such as immune
and malignant cell invasion. [148] Inflammation has response. Non-selectively inhibiting NF-kB may lead
been shown to play a significant role in promoting to severe adverse effects such as immunodeficiency.
cancer metastasis. [149] As NF-kB is a key modulator of Whether such a NF-kB inhibitor will do more harm than
inflammation, it is plausible that chemotherapy-induced good with respect to the immune system in cancer
NF-kB activation may facilitate tumor metastasis patients is likely to depend on the particular target or
by promoting an inflammatory response. Along with combination of targets on which it acts.
pro-inflammatory cytokines, accumulating evidence
also suggests that certain cancer-related microRNAs In this regard, agents selectively targeting NF-kB
may also play important roles in breast cancer signaling activated specifically by DNA damage are
metastasis. [150-152] MicroRNAs are a class of small non- expected to show much greater promise in antagonizing
coding RNAs (~20-24 nucleotides), which primarily therapeutic resistance without compromising the
bind to the 3′-untranslated region (3′-UTR) of target immune system. The recent development of PARP-
mRNA and negatively regulate gene expression at the 1 inhibitors may provide an extraordinary opportunity
post-transcriptional level. [153] Most miRNA genes are for clinical application of such a genotoxic NF-kB
transcribed into primary miRNAs by RNA polymerase selective inhibitor. It has been shown that PARP
II, which can be sequentially processed into precursor, inhibitors significantly augmented cell death in
then mature miRNAs. The transcription of miRNA BRCA1/2-deficient cancer cells, while no overt toxicity
can be regulated by both upstream DNA transcription was observed in normal cells expressing functional
regulatory elements, such as conserved transcription BRCA1/2. [164,165] This effect was termed “synthetic
factor binding sites, and epigenetic modifications. [154] lethality”, which is believed to be a promising “targeted”
Genotoxic stimulation was shown to alter miRNAs strategy to selectively eliminate cancer cells harboring
expression in cancer cells at transcriptional and post- BRCA1/2 mutation while sparing normal cells. [166,167]
transcriptional levels. [155-157] NF-kB has also emerged Currently, FDA has approved the PARP inhibitors
as an important transcription regulator of miRNA olaparib and rucaparib for treating ovarian cancer
genes. [158-161] A recent report showed that genotoxic patients with BRCA mutation. It has been shown that
NF-kB activation regulates the expression of both pro- DNA damage-induced NF-kB activation in human
54 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ March 27, 2017