Page 63 - Read Online
P. 63

Wang et al.                                                                                                                                                                          Genotoxic NF-kB activation in cancer

           cancer cells was significantly attenuated by PARP-1   participants or animals.
           inhibitors. [168]  Moreover, a PARP1 inhibitor, AG-014699
           was shown to sensitize glioma cells to radiation via   REFERENCES
           inhibiting NF-kB activation. [169]  Thus, inhibiting PARP1
           may not only further diminish the DNA repair capacity   1.   Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S. Molecular
           of BRCA-deficient breast cancer cells, but also abolish   mechanisms  of mammalian  DNA repair  and  the  DNA damage
           genotoxic drug-induced NF-kB activation and sensitize   checkpoints. Annu Rev Biochem 2004;73:39-85.
           TNBC patients to chemotherapy.                     2.   Khanna KK, Jackson SP. DNA double-strand breaks: signaling, repair
                                                                 and the cancer connection. Nat Genet 2001;27:247-54.
                                                              3.   De Bont R, van Larebeke N. Endogenous DNA damage in humans: a
           CONCLUSION AND PERSPECTIVE                            review of quantitative data. Mutagenesis 2004;19:169-85.
                                                              4.   Ciccia A, Elledge SJ. The DNA damage response: making it safe to
           The studies on DNA damage response and NF-kB have     play with knives. Mol Cell 2010;40:179-204.
           significantly  improved  our  understanding  of  molecular   5.   d’Adda di Fagagna F. Living on a break: cellular  senescence  as a
           signaling leading to genotoxic NF-kB activation       DNA-damage response. Nat Rev Cancer 2008;8:512-22.
           in the last two decades.  These studies have  also   6.   McCool KW, Miyamoto S. DNA damage-dependent  NF-kappa B
                                                                 activation: NEMO turns nuclear signaling inside out. Immunol Rev
           provided  promising  drug  targets,  such  as  PARP-1,  for   2012;246:311-26.
           selectively inhibiting NF-kB activation by radiation   7.   Sen R, Baltimore D. Inducibility of kappa immunoglobulin enhancer-
           and chemotherapeutics in cancer cells, which may be   binding protein Nf-kappa B by a posttranslational mechanism. Cell
           able to resensitize treatment-refractory cancer cells to   1986;47:921-8.
           conventional chemotherapy. The extension of the period   8.   Sen R, Baltimore  D. Multiple nuclear factors interact  with the
           that cancer patients can benefit from these cost-effective   immunoglobulin  enhancer  sequences.  Cell  1986.  46:  705-716.  J
           “old” chemotherapeutic drugs will also substantially   9.   Immunol 2006;177:7485-96.
                                                                 Baeuerle PA, Baltimore D. I kappa B: a specific inhibitor of the NF-
           alleviate the financial burden the patients bear due to   kappa B transcription factor. Science 1988;242:540-6.
           the high cost of newly developed therapeutic agents.   10.  Ghosh S, Hayden MS. New regulators of NF-kappaB in inflammation.
           Nevertheless, further investigation is still much needed   Nat Rev Immunol 2008;8:837-48.
           to explore the critical downstream NF-kB-target genes   11.  Hayden MS, Ghosh S. Shared principles in NF-kappaB signaling. Cell
           which are specifically induced by DNA damage. Better   2008;132:344-62.
           understanding  of  how  these  induced  genes,  protein   12.  Piret  B, Piette  J.  Topoisomerase  poisons activate  the  transcription
           genes or non-coding RNAs, modulate cell response      factor NF-kappaB in  ACH-2  and CEM cells.  Nucleic  Acids  Res
                                                                 1996;24:4242-8.
           to DNA damage, will help to develop novel therapeutic   13.  Habraken Y, Piret B, Piette J. S phase dependence and involvement
           agents selectively targeting those pro-survival/      of NF-kappaB activating  kinase to NF-kappaB activation  by
           metastatic targets and counteract acquired therapeutic   camptothecin. Biochem Pharmacol 2001;62:603-16.
           resistance. Furthermore, these gene signatures may   14.  Wu ZH, Miyamoto S. Many faces of NF-kappa B signaling induced
           also serve as predictive biomarkers for evaluating the   by genotoxic stress. J Mol Med (Berl) 2007;85:1187-202.
           potential  benefit  and  effectiveness  in  patients  who   15.  Schmitt AM, Crawley CD, Kang S, Raleigh DR, Yu X, Wahlstrom JS,
           receive cytotoxic chemotherapies and radiation.       Voce DJ, Darga TE, Weichselbaum RR, Yamini B. p50 (NF-kappaB1)
                                                                 is an effector protein in the cytotoxic response to DNA methylation
                                                                 damage. Mol Cell 2011;44:785-96.
           Authors’ contributions                             16.  Campbell KJ, Witty JM, Rocha S, Perkins ND. Cisplatin mimics ARF
           The study’s conception  and design: W.  Wang,  A.M.   tumor  suppressor regulation  of  RelA  (p65)  nuclear  factor-kappaB
           Mani, Z.H. Wu                                         transactivation. Cancer Res 2006;66:929-35.
           Paper’s writing: W. Wang, A.M. Mani, Z.H. Wu       17.  Hartlerode AJ, Scully R. Mechanisms of double-strand break repair in
           Manuscripts review and edition: Z.H. Wu               somatic mammalian cells. Biochem J 2009;423:157-68.
                                                              18.  Goodarzi AA, Noon AT, Jeggo PA. The impact of heterochromatin on
                                                                 DSB repair. Biochem Soc Trans 2009;37:569-76.
           Financial support and sponsorship                  19.  Brown JS, O’Carrigan B, Jackson SP, Yap TA. Targeting DNA repair
           The work in the authors’ laboratory has been supported   in cancer: beyond PARP inhibitors. Cancer Discov 2017;7:20-37.
           by NIH R01CA149251 and American Cancer Society     20.  Vilenchik  MM, Knudson  AG. Endogenous DNA double-strand
           (RSG-13-186-01-CSM).                                  breaks: production, fidelity of repair, and induction of cancer. Proc
                                                                 Natl Acad Sci U S A 2003;100:12871-6.
           Conflicts of interest                              21.  Branzei D, Foiani M. Maintaining genome stability at the replication
           There are no conflicts of interest.                   fork. Nat Rev Mol Cell Biol 2010;11:208-19.
                                                              22.  Dillon LW, Burrow AA, Wang YH. DNA instability at chromosomal
           Patient consent                                       fragile sites in cancer. Curr Genomics 2010;11:326-37.
           There is no patient involved.                      23.  Stracker  TH,  Theunissen  JW, Morales M, Petrini  JH.  The  Mre11
                                                                 complex and the metabolism of chromosome breaks: the importance
                                                                 of communicating and holding things together. DNA Repair (Amst)
           Ethics approval                                       2004;3:845-54.
           This article does not contain any studies with human   24.  Lavin MF. ATM and the Mre11 complex combine to recognize and
                           Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ March 27, 2017          55
   58   59   60   61   62   63   64   65   66   67   68