Cancer Letters

Cancer Letters

Volume 231, Issue 2, 18 January 2006, Pages 158-168
Cancer Letters

Mini-Review
NF-κB modulation and ionizing radiation: mechanisms and future directions for cancer treatment

https://doi.org/10.1016/j.canlet.2005.01.022Get rights and content

Abstract

NF-κB transcription factor regulates important cellular processes ranging from establishment of the immune and inflammatory responses to regulation of cell proliferation or apoptosis, through the induction of a large array of target genes.

NF-κB is now considered as an important actor in the tumorigenic process mainly because it exerts strong anti-apoptotic functions in cancer cells. NF-κB is triggered by chimio- and radio-therapeutic strategies that are intended to eliminate cancerous cells through induction of apoptosis. Numerous studies have demonstrated that inhibition of NF-κB by different means increased sensitivity of cancer cells to the apoptotic action of diverses effectors such as TNFα or chemo- or radio-therapies. From these studies as emerged the concept that NF-κB blockade could be associated to conventional therapies in order to increase their efficiency.

This review focuses on the current knowledge on NF-κB regulation and discusses the therapeutic potential of targeting NF-κB in cancer in particular during radiotherapy.

Introduction

NF-κB (Nuclear Factor-κB) was described for the first time in 1986 as a nuclear protein binding to the kappa immunoglobulin-light chain enhancer [1]. Since then, NF-κB has emerged as an ubiquitous factor involved in the regulation of numerous important processes as diverses as immune [2] and inflammatory responses [3], apoptosis [4] and cell proliferation [5]. These last two properties explain the implication of NF-κB in the tumorigenic process as well as the promise of a targeted therapeutic intervention [6]. In the present study, we described in the first part an overview of structure and functions of NF-κB and, in a second part, a focus on ionizing radiation, its impact on NF-κB pathway and the capacity of radiosensitization of NF-κB.

Section snippets

Structure of NF-κB /IKB complexes

Rel/NF-κB transcription factors share a highly conserved 300-amino-acid Rel Homology Domain (RH) containing sequences for dimerization, DNA binding, nuclear translocation and interaction with the inhibitory subunit IKB (Inhibitor of κB) [7], [8]. Rel/NF-κB are organized in two classes. The p105 and p100 proteins of the NF-κB class are synthesized as precursors containing several C-terminal ankyrin repeats that are eliminated during maturation to respectively generate DNA-binding competent

Regulation of NF-κB activity

NF-κB activation is modulated by various different mechanisms involving protein/protein interactions, phosphorylation, and transcriptional modulation.

NF-κB functions

Since its discovery in 1986, NF-κB has primarily been known for its regulatory role for immune and inflammatory responses. Its functions have now been extended to the regulation of cell proliferation and survival and NF-κB is considered as both an important player in the tumorigenic process and a potential therapeutic target in cancer [5], [41], [42].

NF-κB and radioresistance

Radiotherapy acts through the induction of double strand breaks to DNA in order to induce elimination of cancerous cells via programmed cell death [68].

The efficiency of radiotherapy for cancer treatment is limited by toxic side effects impeding dose escalation. Moreover, cancer cells often develop radioresistance mechanisms that are related to the DNA repair response. The aim of combining chemo- to radio-therapy is to strengthen the efficiency of radiation by inhibition of DNA repair, and

Conclusion

NF-κB is now recognized as an important player in several critical steps of the tumorigenic process. Not only NF-κB promotes survival of cancer cells but it also contributes to abnormal proliferation and metastasis. As a stress factor, NF-κB is a crucial element of the cell's protective response to radiations and represents therefore an attractive target in new therapeuticals approaches to fight cancer. The pharmaceutical industry is producing several inhibitors of the NF-κB pathway that are

References (104)

  • S.M. Russo et al.

    Enhancement of radiosensitivity by proteasome inhibition: implications for a role of NF-κB

    Int. J. Radiat. Oncol. Biol. Phys.

    (2001)
  • J. Adams

    Proteasome inhibition: a novel approach to cancer therapy

    Trends. Mol. Med.

    (2002)
  • S. Singh et al.

    Activation of transcription factor NF-kB is suppressed by curcumin (diferulolylmethane)

    J. Biol. Chem.

    (1995)
  • M.M. Chaturvedi et al.

    Sanguinarine (pseudochelerythrine) is a potent inhibitor of NF-κB activation, IkappaBalpha phosphorylation, and degradation

    J. Biol. Chem.

    (1997)
  • T. Hideshima et al.

    NF-κB as a therapeutic target in multiple myeloma

    J. Biol. Chem.

    (2002)
  • E.B. Kopp et al.

    NF-κB and rel proteins in innate immunity

    Adv. Immunol.

    (1995)
  • A. Krikos et al.

    Transcriptional activation of the tumor necrosis factor alpha-inducilble zinc finger protein, A20, is mediated by kappa B elements

    J. Biol. Chem.

    (1992)
  • S. Desagher et al.

    Mitochondria as the central control point of apoptosis

    Trends Cell Biol.

    (2000)
  • R. Wadgaonkar et al.

    CREB-binding protein is a nuclear integrator of nuclear-kappaB and p53 signaling

    J. Biol. Chem.

    (1999)
  • G. Tang et al.

    Blocking caspase-3 mediated proteolysis of IKKβ suppresses TNFα-induced apoptosis

    Mol. Cell

    (2001)
  • L. Li et al.

    Cellular responses to ionizing radiation damage

    Int. J. Radiat. Oncol. Biol. Phys.

    (2001)
  • C.C. Li et al.

    Phosphorylation of NF-KB1-p50 is involved in NF-kappa B activation and stable DNA binding

    J. Biol. Chem.

    (1994)
  • M. Jung et al.

    NF-κB signaling pathway as a target for human tumor radiosensitization

    Semin. Radiat. Oncol.

    (2001)
  • S. Basu et al.

    The DNA-dependent protein kinase participates in the activation of NF-κB following DNA damage

    Biochem. Biophys. Res. Commun.

    (1998)
  • M. Lavin et al.

    Ataxia-telangiectasia: a multifaceted genetic disorder associated with defective signal transduction

    Curr. Opin. Immunol.

    (1996)
  • F. Pajonk et al.

    Apoptosis and radiosensitization of hodgkin cells by proteasome inhibition

    Int. J. Radiat. Oncol. Biol. Phys.

    (2000)
  • U. Raju et al.

    Failure of a second X-ray dose to activate nuclear factor kappaB in normal rat astrocytes

    J. Biol. Chem.

    (1997)
  • C. Didelot et al.

    Constitutive NF-κB activity influences basal apoptosis and radiosensitivity of head-and-neck carcinoma cell lines

    Int. J. Radiat. Oncol. Biol. Phys.

    (2001)
  • F.R. Greten et al.

    links inflammation and tumorigenesis in a mouse model of colitis-associated cancer

    Cell

    (2004)
  • H. Clevers

    At the crossroads of inflammation and cancer

    Cell

    (2004)
  • R. Sen et al.

    Inducibility of k immunoglobulins enhancer-binding protein NF-κB by a posttranslatinal mechanism

    Cell

    (1986)
  • P. Baeuerle et al.

    Function and activation of NF-κB in the immune system

    Annu. Rev. Immunol.

    (1994)
  • P.J. Barnes et al.

    Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases

    N. Engl. J. Med.

    (1997)
  • M. Karin et al.

    NF-κB in cancer: from innocent bystander to major culprit

    Nature Rev. Cancer

    (2002)
  • A.S. Baldwin

    The NF-κB and I kappa B proteins: new discoveries and insights

    Annu. Rev. Immunol.

    (1996)
  • U. Siebenlist et al.

    Structure, regulation and function of NF-κB

    Annu. Rev. Cell Biol.

    (1994)
  • M. Karin et al.

    Phosphorylation meets ubiquitination: the control of NF-κB activity

    Annu. Rev. Immmunol.

    (2000)
  • G. Franzoso et al.

    The oncoprotein Bcl-3 can facilitate NF-kappa B-mediated transactivation by removing inhibiting p50 homodimers from select kappa B sites

    Eur. Mol. Boil. Org. J.

    (1993)
  • G. Ghosh et al.

    Structure of NF-κB p50 homodimer bound to a kappa B site

    Nature

    (1995)
  • H. Pahl

    Activators and target genes of Rel/NF-κB transcription factors

    Oncogene

    (1999)
  • N. Li et al.

    Ionizing radiation and short wavelength UV activate NF-κB through two distinct mechanisms

    Proc. Natl Acad. Sci. USA

    (1998)
  • M. Karin

    How NF-kB is activated: the role of the IkB kinase (IKK) complex

    Oncogene

    (1999)
  • E. Zandi et al.

    Bridging the gap: composition, regulation, and physiological function of the IkappaB kinase complex

    Mol. Cell Biol.

    (1999)
  • S. Sachdev et al.

    Nuclear localization of IkappaB alpha is mediated by the second ankyrin repeat: the IkappaB alpha ankyrin repeats define a novel class of cis-acting nuclear import sequences

    Mol. Cell Biol.

    (1998)
  • T.D. Gilmore

    The Rel/NF-kappaB signal transduction pathway: introduction

    Oncogene

    (1999)
  • C. Beraud et al.

    Involvement of regulatory and catalytic subunits of phosphoinositide 3-kinase in NF-κB activation

    Proc. Natl Acad. Sci. USA

    (1999)
  • C.C. Li et al.

    NF-kappa B/Rel family members are physically associated phosphoproteins

    Biochem. J.

    (1994)
  • N. Sizemore et al.

    Activation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-κB p65/RelA subunit

    Mol. Cell Biol.

    (1999)
  • Y. Yamamoto et al.

    Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer

    J. Clin. Invest.

    (2001)
  • K. Natarajan et al.

    Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-κB

    Proc. Natl Acad. Sci. USA

    (1996)
  • Cited by (167)

    • Dual aspect of radioenhancers and free radical scavengers

      2020, Free Radical Biology and Medicine
      Citation Excerpt :

      Mainly nanoparticles containing high-Z atoms are concerned in this model. A different class of radiosensitizers containing no high-Z atoms, like deoxyglucose or glucocorticoids and many other chemicals, is an active field of studies [11–13]. Such molecules are called metabolic radioenhancers from the induced inhibition of the metabolic cell defences and cell repairs, in presence of these molecules, contributing to the radio enhancement.

    View all citing articles on Scopus
    View full text