NF-kappaB modulation and ionizing radiation: mechanisms and future directions for cancer treatment.

NF-kappaB 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-kappaB is now considered as an important actor in the tumorigenic process mainly because it exerts strong anti-apoptotic functions in cancer cells. NF-kappaB 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-kappaB by different means increased sensitivity of cancer cells to the apoptotic action of diverses effectors such as TNFalpha or chemo- or radio-therapies. From these studies as emerged the concept that NF-kappaB blockade could be associated to conventional therapies in order to increase their efficiency. This review focuses on the current knowledge on NF-kappaB regulation and discusses the therapeutic potential of targeting NF-kappaB in cancer in particular during radiotherapy.

[1]  C. Mueller-Dieckmann,et al.  Tyrosine Phosphorylation of IkB-a Activates NF-kB without Proteolytic Degradation of IkB-a , 1996 .

[2]  John Calvin Reed,et al.  Inhibition of the NF-κB transcription factor increases Bax expression in cancer cell lines , 2001, Oncogene.

[3]  C. Y. Wang,et al.  Requirement of NF-kappaB activation to suppress p53-independent apoptosis induced by oncogenic Ras. , 1997, Science.

[4]  Y. Ben-Neriah,et al.  NF-κB functions as a tumour promoter in inflammation-associated cancer , 2004, Nature.

[5]  Marianne Fillet,et al.  NF-κB transcription factor induces drug resistance through MDR1 expression in cancer cells , 2003, Oncogene.

[6]  David Baltimore,et al.  Inducibility of κ immunoglobulin enhancer-binding protein NF-κB by a posttranslational mechanism , 1986, Cell.

[7]  P. Tofilon,et al.  Failure of a Second X-ray Dose to Activate Nuclear Factor κB in Normal Rat Astrocytes* , 1997, The Journal of Biological Chemistry.

[8]  D. Hallahan,et al.  Membrane-derived second messenger regulates x-ray-mediated tumor necrosis factor alpha gene induction. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[9]  P. Tofilon,et al.  NF kappa B activity and target gene expression in the rat brain after one and two exposures to ionizing radiation. , 1999, Radiation oncology investigations.

[10]  R. Ravi,et al.  CD95 (Fas)-induced Caspase-mediated Proteolysis of NF-κB , 1998 .

[11]  R. Wadgaonkar,et al.  CREB-binding Protein Is a Nuclear Integrator of Nuclear Factor-κB and p53 Signaling* , 1999, The Journal of Biological Chemistry.

[12]  Michael Karin,et al.  IKKβ Links Inflammation and Tumorigenesis in a Mouse Model of Colitis-Associated Cancer , 2004, Cell.

[13]  G. Franzoso,et al.  Structure, regulation and function of NF-kappa B. , 1994, Annual review of cell biology.

[14]  Michael Karin,et al.  NF-κB in cancer: from innocent bystander to major culprit , 2002, Nature Reviews Cancer.

[15]  Hans Clevers,et al.  At the Crossroads of Inflammation and Cancer , 2004, Cell.

[16]  J. Adams.  Proteasome inhibition: a novel approach to cancer therapy. , 2002, Trends in molecular medicine.

[17]  V. Bours,et al.  The oncoprotein Bcl-3 directly transactivates through κB motifs via association with DNA-binding p50B homodimers , 1993, Cell.

[18]  D. Longo,et al.  Phosphorylation of NF-KB1-p50 is involved in NF-kappa B activation and stable DNA binding. , 1994, The Journal of biological chemistry.

[19]  M. Jung,et al.  NF-κB signaling pathway as a target for human tumor radiosensitization , 2001 .

[20]  A. Ciechanover,et al.  Inhibition of NF‐κB cellular function via specific targeting of the IκB‐ubiquitin ligase , 1997 .

[21]  David Baltimore,et al.  Two Pathways to NF-κB , 2002 .

[22]  P. Tofilon,et al.  Radiation-induced activation of nuclear factor-kappaB involves selective degradation of plasma membrane-associated I(kappa)B(alpha). , 2002, Molecular biology of the cell.

[23]  Y. Shiloh,et al.  ATM: A mediator of multiple responses to genotoxic stress , 1999, Oncogene.

[24]  M. Cortés,et al.  ATM and the Catalytic Subunit of DNA-Dependent Protein Kinase Activate NF-κB through a Common MEK/Extracellular Signal-Regulated Kinase/p90rsk Signaling Pathway in Response to Distinct Forms of DNA Damage , 2004, Molecular and Cellular Biology.

[25]  S. Venuta,et al.  CD40 and B Chronic Lymphocytic Leukemia Cell Response To Fludarabine: The Influence of NF-kB/Rel Transcription Factors On Chemotherapy-Induced Apoptosis , 2000, Leukemia & lymphoma.

[26]  M. Story,et al.  Cellular responses to ionizing radiation damage. , 2001, International journal of radiation oncology, biology, physics.

[27]  Nanxin Li,et al.  Ionizing radiation and short wavelength UV activate NF-kappaB through two distinct mechanisms. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Y. Shiloh,et al.  Ataxia-telangiectasia: a multifaceted genetic disorder associated with defective signal transduction. , 1996, Current opinion in immunology.

[29]  P. Baeuerle,et al.  Involvement of regulatory and catalytic subunits of phosphoinositide 3-kinase in NF-kappaB activation. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[30]  F. McCormick,et al.  Transcriptional activation of TRADD mediates p53-independent radiation-induced apoptosis of glioma cells , 2001, Oncogene.

[31]  B. Aggarwal,et al.  Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[32]  J. Piette,et al.  NF-κB activation in response to toxical and therapeutical agents: role in inflammation and cancer treatment , 2000 .

[33]  K. Vousden,et al.  Role of NF-κB in p53-mediated programmed cell death , 2000, Nature.

[34]  T. Gilmore,et al.  The Rel/NF-κB signal transduction pathway: introduction , 1999, Oncogene.

[35]  A. Hoffmann,et al.  Nuclear Localization of IκBα Is Mediated by the Second Ankyrin Repeat: the IκBα Ankyrin Repeats Define a Novel Class of cis-Acting Nuclear Import Sequences , 1998, Molecular and Cellular Biology.

[36]  James B. Mitchell,et al.  Cisplatin and radiation sensitivity in human head and neck squamous carcinomas are independently modulated by glutathione and transcription factor NF‐κB , 2000, Head & neck.

[37]  J. Adams.  The development of proteasome inhibitors as anticancer drugs. , 2004, Cancer cell.

[38]  D. Longo,et al.  NF-kappa B/Rel family members are physically associated phosphoproteins. , 1994, The Biochemical journal.

[39]  M. Barberi-Heyob,et al.  Constitutive NF-κB activity influences basal apoptosis and radiosensitivity of head-and-neck carcinoma cell lines , 2001 .

[40]  P. Tofilon,et al.  Inhibition of radiation-induced nuclear factor-kappaB activation by an anti-Ras single-chain antibody fragment: lack of involvement in radiosensitization. , 2002, Cancer research.

[41]  M. Merville,et al.  Stable inhibition of nuclear factor kappaB in cancer cells does not increase sensitivity to cytotoxic drugs. , 1999, Cancer research.

[42]  Brendan D. Price,et al.  The DNA-Dependent Protein Kinase Participates in the Activation of NFκB Following DNA Damage , 1998 .

[43]  C. Gélinas,et al.  To be, or not to be: NF-κB is the answer – role of Rel/NF-κB in the regulation of apoptosis , 2003, Oncogene.

[44]  David Baltimore,et al.  Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB , 1995, Nature.

[45]  S. Barve,et al.  A high dose of ionizing radiation induces tissue-specific activation of nuclear factor-kappaB in vivo. , 1999, Radiation research.

[46]  J. Wong,et al.  Activation of nuclear factor kappaB in radioresistance of TP53-inactive human keratinocytes. , 2002, Cancer research.

[47]  B. Aggarwal,et al.  Activation of Transcription Factor NF-κB Is Suppressed by Curcumin (Diferuloylmethane) (*) , 1995, The Journal of Biological Chemistry.

[48]  E. Zandi,et al.  Bridging the Gap: Composition, Regulation, and Physiological Function of the IκB Kinase Complex , 1999, Molecular and Cellular Biology.

[49]  A. Kajdacsy-Balla,et al.  The role of constitutive NF-κB activity in PC-3 human prostate cancer cell invasive behavior , 2004, Clinical & Experimental Metastasis.

[50]  B. Aggarwal,et al.  Sanguinarine (Pseudochelerythrine) Is a Potent Inhibitor of NF-κB Activation, IκBα Phosphorylation, and Degradation* , 1997, The Journal of Biological Chemistry.

[51]  P. Auberger,et al.  Blocking NF-κB activation in Jurkat leukemic T cells converts the survival agent and tumor promoter PMA into an apoptotic effector , 2002, Oncogene.

[52]  H. Nakayama,et al.  High expression levels of nuclear factor κB, IκB kinase α and Akt kinase in squamous cell carcinoma of the oral cavity , 2001 .

[53]  V. Bours,et al.  The oncoprotein Bcl‐3 can facilitate NF‐kappa B‐mediated transactivation by removing inhibiting p50 homodimers from select kappa B sites. , 1993, The EMBO journal.

[54]  A. Krikos,et al.  Transcriptional activation of the tumor necrosis factor alpha-inducible zinc finger protein, A20, is mediated by kappa B elements. , 1992, The Journal of biological chemistry.

[55]  J. Martinou,et al.  Mitochondria as the central control point of apoptosis. , 2000, Trends in cell biology.

[56]  Michael Karin,et al.  The Beginning of the End: IκB Kinase (IKK) and NF-κB Activation* , 1999, The Journal of Biological Chemistry.

[57]  E. Kopp,et al.  NF-kappa B and rel proteins in innate immunity. , 1995, Advances in immunology.

[58]  Inder M. Verma,et al.  Severe Liver Degeneration in Mice Lacking the IκB Kinase 2 Gene , 1999 .

[59]  M. Karin,et al.  IκB-kinaseβ-dependent NF-κB activation provides radioprotection to the intestinal epithelium , 2004 .

[60]  Seamus J. Martin,et al.  Suppression of TNF-α-Induced Apoptosis by NF-κB , 1996, Science.

[61]  A. Ivanov,et al.  High constitutive level of NF-κB is crucial for viability of adenocarcinoma cells , 2001, Cell Death and Differentiation.

[62]  T. Gilmore,et al.  Control of apoptosis by Rel/NF-κB transcription factors , 1999, Oncogene.

[63]  E. Gelmann,et al.  Tumor necrosis factor-alpha sensitizes prostate cancer cells to gamma-irradiation-induced apoptosis. , 1999, Cancer research.

[64]  R. Gaynor,et al.  Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. , 2001, The Journal of clinical investigation.

[65]  S. Ghosh,et al.  Phosphorylation of NF-kappa B p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. , 1998, Molecular cell.

[66]  Peter Scheurich,et al.  NF-κB Inducers Upregulate cFLIP, a Cycloheximide-Sensitive Inhibitor of Death Receptor Signaling , 2001, Molecular and Cellular Biology.

[67]  M. Karin,et al.  Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. , 2000, Annual review of immunology.

[68]  Tom Maniatis,et al.  The ubiquitinproteasome pathway is required for processing the NF-κB1 precursor protein and the activation of NF-κB , 1994, Cell.

[69]  G. Sonenshein,et al.  Nuclear factor kappaB cooperates with c-Myc in promoting murine hepatocyte survival in a manner independent of p53 tumor suppressor function. , 1999, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[70]  N. Magné,et al.  Activation of Nuclear Factor κB through the IKK Complex by the Topoisomerase Poisons SN38 and Doxorubicin: A Brake to Apoptosis in HeLa Human Carcinoma Cells , 2001 .

[71]  S. Harrison,et al.  Structure of an IκBα/NF-κB Complex , 1998, Cell.

[72]  Chris Albanese,et al.  NF-κB Controls Cell Growth and Differentiation through Transcriptional Regulation of Cyclin D1 , 1999, Molecular and Cellular Biology.

[73]  Marty W. Mayo,et al.  TNF- and Cancer Therapy-Induced Apoptosis: Potentiation by Inhibition of NF-κB , 1996, Science.

[74]  C. Thompson,et al.  Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and death. , 1998, Genes & development.

[75]  N. Munshi,et al.  NF-κB as a Therapeutic Target in Multiple Myeloma* , 2002, The Journal of Biological Chemistry.

[76]  C. Mueller-Dieckmann,et al.  Tyrosine Phosphorylation of IκB-α Activates NF-κB without Proteolytic Degradation of IκB-α , 1996, Cell.

[77]  M. Kasten,et al.  pRb and the Cdks in apoptosis and the cell cycle , 1998, Cell Death and Differentiation.

[78]  H. Pahl.  Activators and target genes of Rel/NF-κB transcription factors , 1999, Oncogene.

[79]  E. Wright,et al.  Inflammatory-type responses after exposure to ionizing radiation in vivo: a mechanism for radiation-induced bystander effects? , 2001, Oncogene.

[80]  P. Baeuerle,et al.  Function and activation of NF-kappa B in the immune system. , 1994, Annual review of immunology.

[81]  A. Baldwin,et al.  THE NF-κB AND IκB PROTEINS: New Discoveries and Insights , 1996 .

[82]  M. Karin,et al.  Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. , 1997, The New England journal of medicine.

[83]  D. Goeddel,et al.  TNF-R1 Signaling: A Beautiful Pathway , 2002, Science.

[84]  N. Horikoshi,et al.  Indomethacin-induced radiosensitization and inhibition of ionizing radiation-induced NF-kappaB activation in HeLa cells occur via a mechanism involving p38 MAP kinase. , 2001, Cancer research.

[85]  S. Harrison,et al.  Structure of an IkBa/NF-kB Complex , 1998 .

[86]  David Baltimore,et al.  NF-κB: Ten Years After , 1996, Cell.

[87]  A. Dritschilo.  Radiosensitivity and transcription factor NF-kappaB inhibition-progress and pitfalls. , 1999, Journal of the National Cancer Institute.

[88]  G. Stark,et al.  Activation of Phosphatidylinositol 3-Kinase in Response to Interleukin-1 Leads to Phosphorylation and Activation of the NF-κB p65/RelA Subunit , 1999, Molecular and Cellular Biology.

[89]  H. Takebe,et al.  Enhanced radiosensitivity by inhibition of nuclear factor kappa B activation in human malignant glioma cells. , 1996, International journal of radiation biology.

[90]  P. Elliott,et al.  Enhancement of radiosensitivity by proteasome inhibition: implications for a role of NF-kappaB. , 2001, International journal of radiation oncology, biology, physics.

[91]  A. Bowie,et al.  Oxidative stress and nuclear factor-kappaB activation: a reassessment of the evidence in the light of recent discoveries. , 2000, Biochemical pharmacology.

[92]  D. Clarençon,et al.  Acute induction of inflammatory cytokine expression after gamma-irradiation in the rat: effect of an NF-kappaB inhibitor. , 2004, International journal of radiation oncology, biology, physics.

[93]  S. Ghosh,et al.  Inhibition of NF-kappa B by sodium salicylate and aspirin. , 1994, Science.

[94]  Mansoor M Ahmed,et al.  Curcumin confers radiosensitizing effect in prostate cancer cell line PC-3 , 2004, Oncogene.

[95]  P. Sigler,et al.  Structure of NF-κB p50 homodimer bound to a κB site , 1998, Nature.

[96]  W. McBride,et al.  Inhibition of NF-κB, Clonogenicity, and Radiosensitivity of Human Cancer Cells , 1999 .

[97]  Mira Jung,et al.  A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-κB , 1998, Oncogene.

[98]  W. El-Deiry,et al.  p53-mediated repression of nuclear factor-kappaB RelA via the transcriptional integrator p300. , 1998, Cancer research.

[99]  J. Cidlowski,et al.  Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. , 1999, Endocrine reviews.

[100]  D. Boothman,et al.  Coordinate modulation of Sp1, NF‐kappa B, and p53 in confluent human malignant melanoma cells after ionizing radiation , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[101]  J C Reed,et al.  IAP family proteins--suppressors of apoptosis. , 1999, Genes & development.

[102]  W. McBride,et al.  Apoptosis and radiosensitization of hodgkin cells by proteasome inhibition. , 2000, International journal of radiation oncology, biology, physics.

[103]  M. Karin.  How NF-κB is activated: the role of the IκB kinase (IKK) complex , 1999, Oncogene.

[104]  Y. Minemoto,et al.  Blocking Caspase-3-Mediated Proteolysis of IKKβ Suppresses TNF-α-Induced Apoptosis , 2001 .

[105]  B. Piret,et al.  The ATM protein is required for sustained activation of NF-κB following DNA damage , 1999, Oncogene.

[106]  D. Hallahan,et al.  Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation. , 1989, Proceedings of the National Academy of Sciences of the United States of America.