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Restoring apoptosis in pancreatic cancer cells by targeting the nuclear factor-κb signaling pathway with the anti-epidermal growth factor antibody IMC-C225

  • Published:
Journal of Gastrointestinal Surgery

Abstract

We have previously demonstrated that RelA is constitutively activated in the majority of human pancreatic cancers and plays an important role in tumorigenesis and metastasis. The antiapoptotic gene bcl-xl is a downstream target of RelA, and regulation of bcl-xl transcription is mediated directly by the nuclear factor κB (NF-κB) binding sites present in the upstream promoter element of the bcl-xl gene. In this study we investigated the effects of inhibition of epidermal growth factor receptor (EGFR) signaling pathway with the anti-EGFR monoclonal antibody IMC-C225 on constitutive NF-κB activation and regulation of apoptosis-related genes in human pancreatic cancer cells. We found that activation of EGFR can be blocked with the anti-EGFR antibody IMC-C225 in the human pancreatic cancer cell line MDA Panc-28, leading to a marked decrease in constitutive NF-κB DNA binding activity. Our data also suggest that downregulation of NF-κB DNA binding activity by IMC-C225 leads to a decrease in bcl-xl and bfl-1 expression. Therefore, targeting the NF-κB signaling pathway with an anti-EGFR antibody may be one strategy to restore apoptosis in human pancreatic cancer cells, thereby enhancing the effect of chemotherapy and radiation therapy.

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References

  1. Evans DB, Abbruzzese JL, Willett CG. Cancer of the pancreas. In DeVita VT, Hellman S, Rosenberg SA, eds. Cancer, Principles and Practice of Oncology, 6th ed. Philadelphia: Lippincott-Williams & Wilkins, 2001, pp 1126–1161.

  2. Liao Q, Friess H, Kleeff J, Buchler MW. Differential expression of TRAIL-R3 and TRAIL-R4 in human pancreatic cancer. Anticancer Res 2001;21:3153–3159.

    CAS  PubMed  Google Scholar 

  3. Plath T, Peters M, Detjen K, Wetzel M, von Marschall Z, Radke C, Wiedenmann B, Rosewicz S. Overexpression of pRB in human pancreatic carcinoma cells: function in chemotherapy-induced apoptosis. J Natl Cancer Inst 2002;94:129–142.

    Article  CAS  PubMed  Google Scholar 

  4. Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S. Rel/NF-κB/IκB family: Intimate tales of association and dissociation. Genes Dev 1995;9:2723–2735.

    Article  CAS  PubMed  Google Scholar 

  5. Baeuerle PA, Baltimore D. NF-κB: Ten years after. Cell 1996;87:13–20.

    Article  CAS  PubMed  Google Scholar 

  6. Baeuerle PA, Baltimore D. IκB: A specific inhibitor of the NF-κB transcription factor. Science 1988;242:540–546.

    Article  CAS  PubMed  Google Scholar 

  7. Israel A. The IKK complex: An integrator of all signals that activate NF-κB? Trends Cell Biol 2000;10:129–133.

    Article  CAS  PubMed  Google Scholar 

  8. Baldwin AS Jr. The NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol 1996;14:649–683.

    Article  CAS  PubMed  Google Scholar 

  9. Gilmore TD, Koedood M, Piffat KA, White D. Rel/NF-κB/IκB proteins and cancer. Oncogene 1996;13:1367–1378.

    CAS  PubMed  Google Scholar 

  10. Moore BE, Bose HR Jr. Expression of the v-rel oncogene in reticuloendotheliosis virus-transformed fibroblasts. Virology 1988;162:377–387.

    Article  CAS  PubMed  Google Scholar 

  11. Sylla BS, Temin HM. Activation of oncogenicity of the c-rel proto-oncogene. Mol Cell Biol 1986;6:4709–4716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kitajima I, Shinohara T, Bilakovics JDAB, Xu X, Neren-berg M. Ablation of transplanted HTLV-I Tax-transformed tumors in mice by antisense inhibition of NF-κB. Science 1992;258:1792–1795.

    Article  CAS  PubMed  Google Scholar 

  13. Yin MJ, Christerson LB, Yamamoto Y, Kwak YT, Xu S, Mercurio F, Barbosa M, Cobb MH, Gaynor RB. HTLV-I Tax protein binds to MEKK1 to stimulate IκB kinase activity and NF-κB activation. Cell 1998;93:875–884.

    Article  CAS  PubMed  Google Scholar 

  14. Beg AA, Sha WC, Bronson RT, Gosh G, Baltimore D. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB. Nature 1995;376:167–170.

    Article  CAS  PubMed  Google Scholar 

  15. Wang CY, Mayo MW, Baldwin A Jr. TNF- and cancer therapy-induced apoptosis: Potentiation by inhibition of NF-κB. Science 1996;274:784–787.

    Article  CAS  PubMed  Google Scholar 

  16. Van Antwerp D, Martin SJ, Kafri T, Green DR, Verma IM. Suppression of TNF-a-induced apoptosis by NF-κB. Science 1996;274:787–789.

    Article  PubMed  Google Scholar 

  17. Wang W, Larry L, Evans DB, Abbruzzese JL, Chiao PJ. The NF-κB/RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 1999;5:119–127.

    CAS  PubMed  Google Scholar 

  18. Wang W, Abbruzzese J, Evans DB, Chiao PJ. Overexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma is regulated by constitutively activated RelA. Oncogene 1999;18:4554–4563.

    Article  CAS  PubMed  Google Scholar 

  19. Dong DG, Sclabas GM, Fujioka S, Schmidt C, Peng BL, Wu TA, Tsao MS, Evans DB, Abbruzzese JL, McDonnell TJ, Chiao PJ. The function of multiple IκB:NF-κB complexes in the resistance of cancer cells to Taxol-induced Apoptosis. Oncogene 2002;21:6810–6819.

    Article  Google Scholar 

  20. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 2000; 19:6550–6565.

    Article  CAS  PubMed  Google Scholar 

  21. Klapper LN, Kirschbaum MH, Sela M, Yarden Y. Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. Adv Cancer Res 2000;77:25–79.

    Article  CAS  PubMed  Google Scholar 

  22. Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: Receptor heterodimerization in development and cancer. EMBO J 2000; 19:3159–3167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mendelsohn J. Blockade of receptors for growth factors: An anticancer therapy. The Fourth Annual Joseph H. Burche-nal American Association for Cancer Research Clinical Research Award Lecture. Clin Cancer Res 2000;6:747–753.

    CAS  PubMed  Google Scholar 

  24. Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19:183–232.

    Article  CAS  PubMed  Google Scholar 

  25. Uegaki K, Nio Y, Inoue Y, Minari Y, Sato Y, Song MM, Dong M, Tamura K. Clinicopathological significance of epidermal growth factor and its receptor in human pancreatic cancer. Anticancer Res 1997;17:3841–3847.

    CAS  PubMed  Google Scholar 

  26. Yamanaka Y, Friess H, Kobrin MS, Buchler MW, Beger HG, Korc M. Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anticancer Res 1993; 13:565–569.

    CAS  PubMed  Google Scholar 

  27. Habib AA, Chatterjee S, Park SK, Ratan RR, Lefebvre S, Vartanian T. The epidermal growth factor receptor engages receptor interacting protein and nuclear factor-κB (NF-κB)-inducing kinase to activate NF-κB. J Biol Chem 2001;276:8865–8874.

    Article  CAS  PubMed  Google Scholar 

  28. Hirota K, Murata M, Itoh T, Yodoi J, Fukuda K. Redox-sensitive transactivation of epidermal growth factor receptor by tumor necrosis factor confers the NF-κB activation. J Biol Chem 2001;276:25953–25958.

    Article  CAS  PubMed  Google Scholar 

  29. Habib AA, Hognason T, Ren J, Stefansson K, Ratan RR. The epidermal growth factor receptor associates with and recruits phosphatidylinositol 3-kinase to the platelet-derived growth factor beta receptor. J Biol Chem 1998;273:6885–6891.

    Article  CAS  PubMed  Google Scholar 

  30. Obata H, Biro S, Arima N, Kaieda H, Kihara T, Eto H, Miyata M, Tanaka H. NF-kappa B is induced in the nuclei of cultured rat aortic smooth muscle cells by stimulation of various growth factors. Biochem Biophys Res Commun 1996;224:27–32.

    Article  CAS  PubMed  Google Scholar 

  31. Sun L, Carpenter G. Epidermal growth factor activation of NF-κB is mediated through IκBα degradation and intracel-lular free calcium. Oncogene 1998; 16:2095–2102.

    Article  CAS  PubMed  Google Scholar 

  32. Biswas DK, Cruz AP, Gansberger E, Pardee AB. Epidermal growth factor-induced nuclear factor κB activation: A major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells. Proc Natl Acad Sci USA 2000;97:8542–8547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Frazier ML, Fernandez E, deLlorens R, Brown NM, Pathak S, Cleary KR, Abbruzzese JL, Berry K, Olive M, Le-Maistre A, Evans DB. Pancreatic adenocarcinoma cell line, MDA Panc-28 with features of both acinar and ductal cells. Int J Pancreatol 1996;19:31–38.

    Article  CAS  PubMed  Google Scholar 

  34. Andrews NC, Faller DV. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res 1991; 19:2499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Khoshnan A, Tindell C, Laux I, Bae D, Bennett B, Nel AE. The NF-κB cascade is important in bcl-xl expression and for the anti-apoptotic effects of the CD28 receptor in primary human CD4+ lymphocytes. J Immunol 2000;165:1743–1754.

    Article  CAS  PubMed  Google Scholar 

  36. Arlt A, Vorndamm J, Breitenbroich M, Folsch UR, Kalthoff H, Schmidt WE, Schafer H. Inhibition of NF-κB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin. Oncogene 2001;20:859–868.

    Article  CAS  PubMed  Google Scholar 

  37. Wu X, Fan Z, Masui H, Rosen N, Mendelsohn J. Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin. J Clin Invest 1995;95:1897–1905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Peng D, Fan Z, Lu Y, DeBlasio T, Scher H, Mendelsohn J. Anti-epidermal growth factor receptor monoclonal antibody 225 up-regulates p27KIP1 and induces G1 arrest in prostatic cancer cell line DU145. Cancer Res 1996;56:3666–3669.

    CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, ISIS Holcombe Blvd., Box 107, 77030, Houston, TX

    Guido M. Sclabas M.D., Shuichi Fujioka M.D., Ph.D., Christian Schmidt Ph.D., Douglas B. Evans M.D. & Paul J. Chiao Ph.D.

  2. Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

    Zhen Fan M.D.

  3. Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

    Paul J. Chiao Ph.D.

  4. Department of Visceral and Transplantation Surgery, The University of Bern, Inselspital, Bern, Switzerland

    Guido M. Sclabas M.D.

Authors
  1. Guido M. Sclabas M.D.
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  2. Shuichi Fujioka M.D., Ph.D.
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  3. Christian Schmidt Ph.D.
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  4. Zhen Fan M.D.
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  5. Douglas B. Evans M.D.
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  6. Paul J. Chiao Ph.D.
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Correspondence to Paul J. Chiao Ph.D..

Additional information

Supported by The Lockton Fund for Pancreatic Research at the University of Texas M.D. Anderson Cancer Center and The Cancer League of Bern, Switzerland (G.M.S.).

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Sclabas, G.M., Fujioka, S., Schmidt, C. et al. Restoring apoptosis in pancreatic cancer cells by targeting the nuclear factor-κb signaling pathway with the anti-epidermal growth factor antibody IMC-C225. J Gastrointest Surg 7, 37–43 (2003). https://doi.org/10.1016/S1091-255X(02)00088-4

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  • DOI: https://doi.org/10.1016/S1091-255X(02)00088-4

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