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Der Arylhydrocarbon Rezeptor als neue Zielscheibe zur Behandlung des Pankreaskarzinoms

  • J. Kleeff
  • H. Friess
  • A. Koliopanos
  • S. Safe
  • A. Zimmermann
  • M. W. Büchler
Conference paper
Part of the Deutsche Gesellschaft für Chirurgie book series (DTGESCHIR, volume 31)

Abstract

The arylhydrocarbon receptor (AhR) was initially identified as a member of the adaptive metabolic and toxic response pathway to polycyclic aromatic hydrocarbons and to halogenated dibenzo-p-dioxins and dibenzofurans. In the present study, we sought to determine the functional significance of the AhR pathway in pancreatic carcinogenesis. AhR expression was analyzed by Northern blotting. The exact site of AhR expression was analyzed by in situ hybridization and immunohistochemistry. The effects of four selective AhR modulators on pancreatic cancer cell lines were investigated by growth assays, apoptosis assays, and induction of the cyclin-dependent kinase inhibitor p2l. There was strong AhR mRNA expression in pancreatic cancer samples, weak expression in chronic pancreatitis tissues, and faint expression in all normal pancreata. In pancreatic cancer tissues, AhR mRNA and protein expression were localized in the cytoplasm of pancreatic cancer cells. The four AhR agonists inhibited pancreatic cancer cell growth in a dose-dependent manner, and decreased anchorage-independent cell growth. DAPI staining did not reveal nuclear fragmentation and CYP1A1 was not induced by AhR agonists. In contrast, AhR agonists induced the expression of the cyclin-dependent kinase inhibitor p2l. In conclusion, the relatively non-toxic AhR agonists cause growth inhibition in pancreatic cancer cells with high AhR expression levels via cell cycle arrest. Inasmuch as almost all human pancreatic cancer tissues express this receptor at high levels, these or related compounds may play a role in the therapy of pancreatic cancer in the future.

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Literatur

  1. 1.
    Parker SL, Tong T, Bolden S, Wingo PA (1997) Cancer statistics, 1997. CA Cancer J Clin 47: 5–27PubMedCrossRefGoogle Scholar
  2. 2.
    Neoptolemos JP, Stocken DD, Dunn JA, Almond J, Beger HG, Pederzoli P, Bassi C, Dervenis C, Fernandez-Cruz L, Lacaine F, Buckels J, Deakin M, Adab FA, Sutton R, Imrie C, Ihse I, Tihanyi T, Olah A, Pedrazzoli S, Spooner D, Kerr DJ, Friess H, Büchler MW (2001) Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial. Ann Surg. 234: 758–768PubMedCrossRefGoogle Scholar
  3. 3.
    Safe S (2001) Molecular biology of the Ah receptor and its role in carcinogenesis. Toxicol 120: 1–7Google Scholar
  4. 4.
    Steenland K, Piacitelli L, Deddens J, Fingerhut M, Chang LI (1999) Cancer, heart disease, and diabetes in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Natl Cancer Inst 91: 779–786PubMedCrossRefGoogle Scholar
  5. 5.
    Vang O, Jensen MB, Autrup H (1990) Induction of cytochrome P450IA1 in rat colon and liver by indole-3-carbinol and 5,6-benzoflavone. Carcinogenesis 11: 1259–1263PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • J. Kleeff
    • 1
    • 4
  • H. Friess
    • 1
  • A. Koliopanos
    • 1
  • S. Safe
    • 2
  • A. Zimmermann
    • 3
  • M. W. Büchler
    • 1
  1. 1.Abteilung Allgemeine, Viszerale, Unfallchirurgie und Poliklinik, Chirurgische UniversitätsklinikUniversität HeidelbergGermany
  2. 2.Department of Veterinary Physiology and Pharmacology and Department of Biochemistry and BiophysicsTexas A&M UniversityUSA
  3. 3.Institut für PathologieUniversität Bern, InselspitalBernSchweiz
  4. 4.Abteilung Allgemeine, Viszerale, Unfallchirurgie und Poliklinik, Chirurgische UniversitätsklinikUniversität HeidelbergHeidelbergGermany

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