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Wang et al. Genotoxic NF-kB activation in cancer

creating breaks on DNA backbone, and forming cross- DSB AND DNA DAMAGE SIGNALING
links between DNA strands and proteins. Failure to
repair these lesions can lead to genomic instability and DSB is the most severe form of genomic lesion due
detrimental consequences. Breaks on both strands to the potential errors incurred during DSB repair.
[1]
of DNA (double-stranded break, DSB) represent one Cells are equipped with several repair mechanisms
of the most lethal types of genomic lesion, which has including homologous recombination (HR), classical
been associated with pathogenesis of a variety of non-homologous end joining (cNHEJ), back-
[2]
human diseases and aging. DSB can be induced up alternative NHEJ (aNHEJ) and single-strand
by environmental exposure such as ultraviolet (UV) annealing. [4,17-19] Successful HR is generally error-free
or ionizing radiation (IR), as well as by endogenous while NHEJ and other alternative forms of DNA repair
agents like reactive oxygen species generated by cell are more likely to introduce DNA lesions. Most DSBs
metabolism. [3] Genomic lesions can be recognized are repaired quickly, but those DSBs which repaired
and labeled by recruitment of sensor proteins, which incorrectly or escaped repair mechanisms could cause
activates a complex network of cellular responses chromosomal aberrations, loss of heterozygosity,
known as DNA damage response (DDR) and oncogenic mutation, or cell death.
mobilizes DNA repair machinery in order to maintain
genomic integrity. Low levels of DNA damage cause Endogenous and exogenous causes of DSBs
[4]
cell cycle arrest and promote repair of DNA lesions, DSB can be induced by endogenous molecules
whereas severe DNA damage leads to apoptosis or such as reactive oxygen species, lipid peroxides,
permanent cell cycle arrest (senescence) to avoid endogenous reactive chemicals (e.g. aldehydes
neoplastic transformation. DDR is often deregulated and S-adenosylmethionine), telomere attrition and
[5]
in malignant cells, which allows them to escape depurination mechanism. [3] Physiological DSB can
apoptosis or senescence. These cells could proliferate also be generated during V(D)J recombination of
while harboring DNA lesions, which significantly immunoglobin chains in lymphocytes. [20] Moreover,
increases the chance of genetic mutation. A number DSBs are also formed indirectly from collapse of
of anti-apoptotic signaling pathways, such as nuclear stalled transcription forks or arrested replication forks.
factor kappa B (NF-kB), have been shown to also play These replication fork arrests could occur during
critical roles in modulating cancer cell response to normal replication at sequences which are prone to
DNA damage. [6] form secondary structures such as tRNA genes and
chromosomal fragile sites. [21,22]
NF-kB is a family of transcription factors that play
critical roles in inflammation, immunity, cell proliferation, Genotoxic agents are present in the environment at a
development, survival and apoptosis. [7-9] The inactive very low level, whereas higher levels can be found in
NF-kB is present in the cytoplasm in most cell types diagnostic tools and tumor therapies. The exogenous
and it can be activated by a variety of extra-cellular causes of DSBs are mostly either accidental exposure
stimuli such as pro-inflammatory cytokines, bacterial or medical procedures. A harmful dose of IR is normally
lipopolysaccharides, and viral RNA and DNA, via the not present in the environment, but such a dose could
activation of membrane and cytosolic receptors. [10,11] be received from accidental exposure to radioactive
NF-kB was also shown to be activated by DNA materials or, theoretically, a nuclear attack. IR at a dose
damaging drugs in a membrane receptor-independent of 1 Gy leads to approximately 1,000 SSBs and 20-40
manner, which involves a retrograde signaling cascade DSBs per cell, among which DSBs are more cytotoxic
from nucleus to cytoplasm. [6,12-14] It has been reported although less in the number of breaks. Keep in mind
[4]
that NF-kB was activated in response to a variety of that diagnostic imaging techniques such as X-rays and
DNA lesions, such as temozolomide-induced S 1- mammograms use a very low level of radiation which
N
methylation, cisplatin-induced DNA cross-linking, [16] could induce DSB directly and indirectly via oxidative
[15]
and IR-induced DSB. Recent studies have revealed stress. In addition, radiation therapy and cytotoxic
a variety of roles of DNA damage-activated NF-kB in chemotherapeutic drugs, such as camptothecin,
cancer cell responses to radiation and chemotherapies doxorubicin and daunorubicin, induce DSBs in cancer
as well as in cancer progression and metastasis. cells through directly damaging DNA or interfering
This review will focus on the recent progress in DNA topoisomerase function, leading to apoptosis and
understanding DNA damage-induced signaling, DDR, elimination of malignant cells.
and genotoxic DSB agent-induced NF-kB signaling
cascade, as well as their physiological functions DNA damage response
and pathological significance in cancer progression, Damage to DNA can elicit a complex cellular response
therapeutic resistance and metastasis. by activating multiple signaling cascades, which are
46 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ March 27, 2017