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Nuklearmedizin 2010; 49(S 01): S26-S30
DOI: 10.1055/s-0038-1626525
Review
Schattauer GmbH

Membranrezeptorsignale und Kontrolle der DNA-Reparatur nach ionisierender Strahlung

Article in several languages: English | deutsch
M. Toulany
1   Division of Radiobiology & Molecular Environmental Research, Dept. of Radiation Oncology, Eberhard Karls University Tuebingen, Germany
,
H. P. Rodemann
1   Division of Radiobiology & Molecular Environmental Research, Dept. of Radiation Oncology, Eberhard Karls University Tuebingen, Germany
› Author Affiliations
Further Information

Publication History

received: 27 October 2010

accepted: 28 October 2010

Publication Date:
24 January 2018 (online)

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Zusammenfassung

Zahlreiche präklinische und klinische Ergebnisse belegen, dass die Aktivität von erbBRezeptoren, die in Zellen solider Tumore einerseits durch Mutation oder durch Genamplifikation und somit Überexpression der Rezeptoren gegeben sein kann, sowohl für Chemoals Radiotherapie-Resistenz verantwortlich ist. In diesem Zusammenhang induzieren Signalkaskaden, die z. B. durch den epidermalen Wachstumsfaktor-Rezeptor EGFR (erbB1) im Falle seiner abnormalen Aktivität stimuliert werden, spezifische Zellüberlebensmechanismen, durch die eine Resistenz gegen ionisierende Strahlung verursacht wird. Verschiedene In-vitro- und In-vivo-Studien belegen, dass durch so genannte molekulare Targeting-Strategien, die gegen den EGFR gerichtet sind, die Radiotoxizität der Strahlentherapie verstärkt werden kann. Hierbei korreliert der radiosensitivierende Effekt von EGFR-Antagonisten primär mit einer Unterdrückung der Kapazität von Tumorzellen für die Reparatur strahleninduzierter DNA-Doppelstrangbrüche, die über den nicht homologen End-Joining-Reparaturmechanismus ablaufen.

In dieser Übersicht wird die Rolle und Bedeutung des EGFR und erbB2-Rezeptors in der Transduktion strahleninduzierte Signale über die PI3K-Akt-Kaskade und die Beeinflussung der DNA-Doppelstrangbruchreparatur durch diesen Signalweg besprochen und die radiosensitivierenden Effekte entsprechender Antagonisten diskutiert. Das zunehmende Verständnis des mechanistischen Prinzips, wie erbB-Rezeptor-Signalwege in die Regulation der DNADoppelstrangbruchreparatur eingreifen, wird translationelle Ansätze zur Überprüfung neuer Strategien für die klinische Anwendung des molekularen Targeting stimulieren.

Schlüsselwörter

EGFR - PI3K-Akt-Signaltransduktion - DNAReparatur - Strahlenreaktion
 

  • References

  • 1 Ang KK, Berkey BA, Tu X. et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 2002; 62: 7350-7356.
    PubMedGoogle Scholar
  • 2 Bernhard EJ, Stanbridge EJ, Gupta S. et al. Direct evidence for the contribution of activated N-ras and K-ras oncogenes to increased intrinsic radiation resistance in human tumor cell lines. Cancer Res 2000; 60: 6597-6600.
    PubMedGoogle Scholar
  • 3 Bonner JA, Buchsbaum DJ, Russo SM. et al. Anti-EGFR-mediated radiosensitization as a result of augmented EGFR expression. Int J Radiat Oncol Biol Phys 2004; 59: 2-10.
    CrossrefPubMedGoogle Scholar
  • 4 Bonner JA, Harari PM, Giralt J. et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354: 567-578.
    CrossrefPubMedGoogle Scholar
  • 5 Bonner JA, Harari PM, Giralt J. et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer. Lancet Oncol 2010; 11: 21-28.
    CrossrefPubMedGoogle Scholar
  • 6 Bozulic L, Surucu B, Hynx D. et al. PKBalpha/Akt1 acts downstream of DNA-PK in the DNA doublestrand break response and promotes survival. Mol Cell 2008; 30: 203-213.
    CrossrefPubMedGoogle Scholar
  • 7 Cengel KA, Voong KR, Chandrasekaran S. et al. Oncogenic K-Ras signals through epidermal growth factor receptor and wild-type H-Ras to promote radiation survival in pancreatic and colorectal carcinoma cells. Neoplasia 2007; 9: 341-348.
    CrossrefPubMedGoogle Scholar
  • 8 Chan DW, Chen BP, Prithivirajsingh S. et al. Autophosphorylation of the DNA-dependent protein kinase catalytic subunit is required for rejoining of DNA double-strand breaks. Genes Dev 2002; 16: 2333-2338.
    CrossrefPubMedGoogle Scholar
  • 9 Chen BP, Uematsu N, Kobayashi J. et al. Ataxia telangiectasia mutated (ATM) is essential for DNA-PKcs phosphorylations at the Thr-2609 cluster upon DNA double strand break. J Biol Chem 2007; 282: 6582-6587.
    CrossrefPubMedGoogle Scholar
  • 10 Dent P, Yacoub A, Contessa J. et al. Stress and radiation-induced activation of multiple intracellular signaling pathways. Radiat Res 2003; 159: 283-300.
    CrossrefPubMedGoogle Scholar
  • 11 Dittmann K, Mayer C, Fehrenbacher B. et al. Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase. J Biol Chem 2005; 280: 31182-31189.
    CrossrefPubMedGoogle Scholar
  • 12 Feng J, Park J, Cron P. et al. Identification of a PKB/ Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. J Biol Chem 2004; 279: 41189-41196.
    CrossrefPubMedGoogle Scholar
  • 13 Gupta AK, Bakanauskas VJ, Cerniglia GJ. et al. The Ras radiation resistance pathway. Cancer Res 2001; 61: 4278-4282.
    PubMedGoogle Scholar
  • 14 Hatanpaa KJ, Burma S, Zhao D. et al. Epidermal growth factor receptor in glioma. Neoplasia 2010; 12: 675-684.
    CrossrefPubMedGoogle Scholar
  • 15 Huang SM, Harari PM. Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas. Clin Cancer Res 2000; 6: 2166-2174.
    PubMedGoogle Scholar
  • 16 Iliakis G, Wang H, Perrault AR. et al. Mechanisms of DNA double strand break repair and chromosome aberration formation. Cytogenet Genome Res 2004; 104: 14-20.
    CrossrefPubMedGoogle Scholar
  • 17 Kao GD, Jiang Z, Fernandes AM. et al. Inhibition of phosphatidylinositol-3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation. J Biol Chem 2007; 282: 21206-21212.
    CrossrefPubMedGoogle Scholar
  • 18 Khanna KK, Jackson SP. DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 2001; 27: 247-254.
    CrossrefPubMedGoogle Scholar
  • 19 Krause M, Zips D, Thames HD. et al. Preclinical evaluation of molecular-targeted anticancer agents for radiotherapy. Radiother Oncol 2006; 80: 112-122.
    CrossrefPubMedGoogle Scholar
  • 20 Lerdrup M, Bruun S, Grandal MV. et al. Endocytic down-regulation of ErbB2 is stimulated by cleavage of its C-terminus. Mol Biol Cell 2007; 18: 3656-3666.
    CrossrefPubMedGoogle Scholar
  • 21 Lobrich M, Jeggo PA. The impact of a negligent G2/M checkpoint on genomic instability and cancer induction. Nat Rev Cancer 2007; 7: 861-869.
    CrossrefPubMedGoogle Scholar
  • 22 McKenna WG, Muschel RJ, Gupta AK. et al. The RAS signal transduction pathway and its role in radiation sensitivity. Oncogene 2003; 22: 5866-5875.
    CrossrefPubMedGoogle Scholar
  • 23 Molina MA, Codony-Servat J, Albanell J. et al. Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res 2001; 61: 4744-4749.
    PubMedGoogle Scholar
  • 24 Mukherjee B, Choy H, Nirodi C. et al. Targeting nonhomologous end-joining through epidermal growth factor receptor inhibition. Semin Radiat Oncol 2010; 20: 250-257.
    CrossrefPubMedGoogle Scholar
  • 25 Mukherjee B, McEllin B, Camacho CV. et al. EGFRvIII and DNA double-strand break repair. Cancer Res 2009; 69: 4252-4259.
    CrossrefPubMedGoogle Scholar
  • 26 Nyati MK, Morgan MA, Feng FY. et al. Integration of EGFR inhibitors with radiochemotherapy. Nat Rev Cancer 2006; 6: 876-885.
    CrossrefPubMedGoogle Scholar
  • 27 Rodemann HP, Blaese MA. Responses of normal cells to ionizing radiation. Semin Radiat Oncol 2007; 17: 81-88.
    CrossrefPubMedGoogle Scholar
  • 28 Rodemann HP, Dittmann K, Toulany M. Radiation-induced EGFR-signaling and control of DNA-damage repair. Int J Radiat Biol 2007; 83: 781-791.
    CrossrefPubMedGoogle Scholar
  • 29 Sarbassov DD, Guertin DA, Ali SM. et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307: 1098-1101.
    CrossrefPubMedGoogle Scholar
  • 30 Tanaka T, Munshi A, Brooks C. et al. Gefitinib radiosensitizes non-small cell lung cancer cells by suppressing cellular DNA repair capacity. Clin Cancer Res 2008; 14: 1266-1273.
    CrossrefPubMedGoogle Scholar
  • 31 Toker A, Newton AC. Akt/protein kinase B is regulated by autophosphorylation at the hypothetical PDK-2 site. J Biol Chem 2000; 275: 8271-8274.
    CrossrefPubMedGoogle Scholar
  • 32 Toulany M, Baumann M, Rodemann HP. Stimulated PI3K-AKT signaling mediated through ligand or radiation-induced EGFR depends indirectly, but not directly, on constitutive K-Ras activity. Mol Cancer Res 2007; 5: 863-872.
    CrossrefPubMedGoogle Scholar
  • 33 Toulany M, Dittmann K, Baumann M. et al. Radiosensitization of Ras-mutated human tumor cells in vitro by the specific EGF receptor antagonist BIBX1382BS. Radiother Oncol 2005; 74: 117-129.
    CrossrefPubMedGoogle Scholar
  • 34 Toulany M, Dittmann K, Fehrenbacher B. et al. PI3K-Akt signaling regulates basal, but MAP-kinase signaling regulates radiation-induced XRCC1 expression in human tumor cells in vitro. DNA Repair (Amst) 2008; 7: 1746-1756.
    CrossrefPubMedGoogle Scholar
  • 35 Toulany M, Dittmann K, Kruger M. et al. Radioresistance of K-Ras mutated human tumor cells is mediated through EGFR-dependent activation of PI3K-AKT pathway. Radiother Oncol 2005; 76: 143-150.
    CrossrefPubMedGoogle Scholar
  • 36 Toulany M, Kasten-Pisula U, Brammer I. et al. Blockage of epidermal growth factor receptorphosphatidylinositol 3-kinase-AKT signaling increases radiosensitivity of K-RAS mutated human tumor cells in vitro by affecting DNA repair. Clin Cancer Res 2006; 12: 4119-4126.
    CrossrefPubMedGoogle Scholar
  • 37 Toulany M, Kehlbach R, Florczak U. et al. Targeting of AKT1 enhances radiation toxicity of human tumor cells by inhibiting DNA-PKcs-dependent DNA double-strand break repair. Mol Cancer Ther 2008; 7: 1772-1781.
    CrossrefPubMedGoogle Scholar
  • 38 Toulany M, Lee K, Fattah K. et al. Akt is an important mediator for the function of DNA-PK in DNA damage repair and post-irradiation survival. Clin Cancer Res (submitted)..
    Google Scholar
  • 39 Toulany M, Minjgee M, Kehlbach R. et al. ErbB2 expression through heterodimerization with erbB1 is necessary for ionizing radiation-but not EGF-induced activation of Akt survival pathway. Radiother Oncol. 2010 doi: 10.1016/j.radonc.2010.03.008.
    PubMedGoogle Scholar
  • 40 Viniegra JG, Martinez N, Modirassari P. et al. Full activation of PKB/Akt in response to insulin or ionizing radiation is mediated through ATM. J Biol Chem 2005; 280: 4029-4036.
    CrossrefPubMedGoogle Scholar
  • 41 Yacoub A, McKinstry R, Hinman D. et al. Epidermal growth factor and ionizing radiation up-regulate the DNA repair genes XRCC1 and ERCC1 in DU145 and LNCaP prostate carcinoma through MAPK signaling. Radiat Res 2003; 159: 439-452.
    CrossrefPubMedGoogle Scholar
  • 42 Yacoub A, Park JS, Qiao L. et al. MAPK dependence of DNA damage repair. Int J Radiat Biol 2001; 77: 1067-1078.
    CrossrefPubMedGoogle Scholar
  • 43 Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2: 127-137.
    CrossrefPubMedGoogle Scholar
  • 44 Zhang J, Lodish HF. Identification of K-ras as the major regulator for cytokine-dependent Akt activation in erythroid progenitors in vivo. Proc Natl Acad Sci USA 2005; 102: 14605-14610.
    CrossrefPubMedGoogle Scholar