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Inhibition of TRAIL-induced apoptosis by IL-8 is mediated by the p38-MAPK pathway in OVCAR3 cells

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Abstract

Introduction: TRAIL (TNF-Related Apoptosis Inducing Ligand) is a member of the TNF superfamily of cell death inducing ligands. Interestingly, while malignant cells are responsive to TRAIL-induced cell death when used alone or in combination with other agents, normal cells do not appear to be sensitive to this ligand, making it a desirable therapeutic compound against many cancers, including many ovarian carcinomas. Interleukin-8 (IL-8), a member of the C-X-C chemokine family, has been found to be at significantly higher level in the ascites from patients with ovarian cancer. We have previously demonstrated a role for IL-8 in blocking TRAIL's ability to induce apoptosis in the ovarian cancer cell line, OVCAR3, possibly by repressing the DR4 TRAIL receptor expression and blocking caspase-8 cleavage. In addition, we showed a member of the mitogen-activated protein kinase (MAPK) superfamily, p38γ, is among the genes regulated in OVCAR3 cells by TRAIL and IL-8. The present study further investigates involvement of the p38 MAPK pathway in IL-8's ability to block TRAIL-induced apoptosis in the ovarian surface epithelial cancer cell line, OVCAR3.

Results: In this study we demonstrate that p38γ as well as p38α play a significant role in IL-8's ability to block TRAIL-induced apoptosis. Through array analysis, as well as confirmation with other methods, we detected regulation of p38γ and p38α following treatment of the cancer cell line with IL-8 or TRAIL. We also tested two other isoforms of p38 MAPK, p38β and p38δ, but did not find significant regulation by IL-8 or TRAIL. We also examined activation of the p38 MAPK pathway, up-stream as well as down-stream, and noticed activation of the pathway following treatment with TRAIL and decreased activity when IL-8 was introduced. With the use of specific inhibitors, we were able to further confirm the role of this pathway in TRAIL-induced apoptosis, and IL-8's ability to block this apoptosis, in ovarian cancer cell lines.

Conclusion: Taken together, these results further solidify the role of IL-8 in blocking the TRAIL-induced apoptosis in these ovarian carcinoma cells and provide new molecular insight into this potentially important therapeutic target.

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References

  1. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin 1998; 48: 6–29.

    CAS  PubMed  Google Scholar 

  2. Greenlee R, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin 2000; 50: 7–33.

    CAS  PubMed  Google Scholar 

  3. Qazi F, McGuire W. The treatment of epithelial ovarian cancer. CA Cancer J Clin 1995; 15: 88–101.

    Google Scholar 

  4. Steller H. Mechanisms and genes of cellular suicide. Science 1995; 267(5203): 1445–1449.

    CAS  PubMed  Google Scholar 

  5. Jacobson MD, Weil M, Raff MC. Programmed cell death in animal development. Cell 1997; 88(3): 347–354.

    Article  CAS  PubMed  Google Scholar 

  6. Nagata S. Apoptosis by death factor. Cell 1997; 88: 355–365.

    Article  CAS  PubMed  Google Scholar 

  7. Cosman D. A family of ligands for the TNF receptor superfamily. Stem Cells 1994; 12(5): 440–455.

    CAS  PubMed  Google Scholar 

  8. Smith CA, Farrah T, Goodwin RG. The TNF receptor superfamily of cellular and viral proteins: Activation, costimulation, and death. Cell 1994; 76(6): 959–962.

    Article  CAS  PubMed  Google Scholar 

  9. Nagata S, Golstein P. The Fas death factor. Science 1995; 267(5203): 1449–1456.

    CAS  PubMed  Google Scholar 

  10. Amakawa R, Hakem A, Kundig TM, et al. Impaired negative selection of T cells in Hodgkin's disease antigen CD30-deficient mice. Cell 1996; 84(4): 551–562.

    Article  CAS  PubMed  Google Scholar 

  11. Lynch DH, Ramsdell F, Alderson MR. Fas and FasL in the homeostatic regulation of immune responses. Immunology Today 1995; 16(12): 569–574.

    Article  CAS  PubMed  Google Scholar 

  12. Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science 1995; 267(5203): 1456–1462.

    CAS  PubMed  Google Scholar 

  13. Van Parijs L, Abbas AK. Role of Fas-mediated cell death in the regulation of immune responses. Curr Opin Immunol 1996; 8(3): 355–361.

    Article  CAS  PubMed  Google Scholar 

  14. Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995; 3(6): 673–682.

    Article  CAS  PubMed  Google Scholar 

  15. Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 1996; 271(22): 12687–12690.

    CAS  PubMed  Google Scholar 

  16. Marsters SA, Sheridan JP, Pitti RM, et al. A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr Biol 1997; 7(12): 1003–1006.

    Article  CAS  PubMed  Google Scholar 

  17. Rieger J, Ohgaki H, Kleihues P, Weller M. Human astrocytic brain tumors express AP02L/TRAIL. Acta Neuropathologica 1999; 97(1): 1–4.

    Article  CAS  PubMed  Google Scholar 

  18. Emery JG, McDonnell P, Burke MB, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998; 273(23): 14363–14367.

    Article  CAS  PubMed  Google Scholar 

  19. Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 1997; 277(5327): 815–818.

    Article  CAS  PubMed  Google Scholar 

  20. Sheridan JP, Marsters SA, Pitti RM, et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 1997; 277(5327): 818–821.

    Article  CAS  PubMed  Google Scholar 

  21. Ashkenazi A, Pai RC, Fong S, et al. Safety and anti-tumor activity of recombinant soluble Apo2 ligand. J Clinical Inv 1999; 104(2): 155–162.

    CAS  Google Scholar 

  22. Walczak H, Miller RE, Ariail K, et al. Tumoricidal activity of tumor necrosis factor- related apoptosis-inducing ligand in vivo. Nature Medicine 1999; 5(2): 157–163.

    CAS  PubMed  Google Scholar 

  23. Cuello M, Ettenberg SA, Nau MM, Lipkowitz S. Synergistic induction of apoptosis by the combination of trail and chemotherapy in chemoresistant ovarian cancer cells. Gyn Oncol 2001; 81(3): 380–390.

    Article  CAS  Google Scholar 

  24. Lancaster JM, Sayer R, Blanchette C, et al. High expression of Tumor necrosis factor apoptosis- inducing ligand is associated with favorable ovarian cancer survival. Clin Can Res 2003; 9: 762–766.

    CAS  Google Scholar 

  25. Tuschil A, Lam C, Haslberger A, Lindley I. IL-8 stimulates calcium transients and promotes epidermal cell proliferation. Invest Dermatol 1992; 99: 294–298.

    Article  CAS  Google Scholar 

  26. Schadendorf D, Moller A, Algermissen B, Worm M, Sticherling M, Czarnetzki BM. IL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor. J Immunol 1994; 151: 2667–2675.

    Google Scholar 

  27. Miyamoto M, Shimizu Y, Okada K, Kashii Y, Higuchi K, Watanabe A. Effect of interleukin-8 on production of tumor-associated substances and autocrine growth of human liver and pancreatic cancer cells. Can Immunol & Immunother 1998; 47: 47–57.

    CAS  Google Scholar 

  28. Koch AE, Polverini PJ, Kunkel SL, et al. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 1992; 258: 1798–1801.

    CAS  PubMed  Google Scholar 

  29. Singh RK, Gutman M, Reich R, Bar-Eli M. Ultraviolet B irradiation promotes tumorigenic and metastatic properties in primary cutaneous melanoma via induction of interleukin 8. Cancer Research 1995; 55: 3669–3674.

    CAS  PubMed  Google Scholar 

  30. Yatsunami J, Tsuruta N, Ogata K, et al. Interleukin-8 participates in angiogenesis in non-small cell, but not small cell carcinoma of the lung. Cancer Letters 1997; 120: 101–108.

    Article  CAS  PubMed  Google Scholar 

  31. Brew R, Southern SA, Flanagan BF, McDicken IW, Christmas SE. Detection of interleukin-8 mRNA and protein in human colorectal carcinoma cells. Eur J Cancer 1996; 32A: 2142–2147.

    CAS  PubMed  Google Scholar 

  32. Brew R, Erikson JS, West DC, Flanagan BF, Christmas SE. Interleukin-8 as a growth factor for human colorectal carcinoma cells in vitro. Biochem Soc Trans 1997; 25: 264S–2647S.

    CAS  PubMed  Google Scholar 

  33. Kitadai Y, Radinsky R, Bucana CD, et al. Regulation of carcinoembryonic antigen expression in human colon carcinoma cells by the organ microenvironment. Amer J Path 1996; 149: 1157–1166.

    CAS  PubMed  Google Scholar 

  34. Merogi AJ, Marrogi AJ, Ramesh R, Robinson WR, Fermin CD, Freeman SM. Tumor-host interaction: Analysis of cytokines, growth factors, and tumor-infiltrating lymphocytes in ovarian carcinomas. Hum Path 1997; 28: 321–331.

    CAS  PubMed  Google Scholar 

  35. Yoneda J, Kuniyasu H, Crispens MA, Price JE, Bucana CD, Fidler IJ. Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice. J Natl Cancer Inst. 1998; 90: 447–454.

    Article  CAS  PubMed  Google Scholar 

  36. . Abdollahi T, Robertson N, Abdollahi A, Litwack G. Identification of Interleukin-8 as an Inhibitor of TRAIL-induced Apoptosis in the Ovarian Carcinoma Cell Line, OVCAR3. Can Res 2003; 63(15): 4521–4526.

    CAS  Google Scholar 

  37. Waskiewicz AJ, Cooper JA. Mitogen activated protein kinase (MAPK) signal transduction. Curr Opin Cell Biol 1995; 7: 798–805.

    Article  CAS  PubMed  Google Scholar 

  38. Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell 2000; 103: 239–252.

    Article  CAS  PubMed  Google Scholar 

  39. Hibi M, Lin A, Smeal T, Minden A, Karin M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes & Development 1993; 7(11): 2135–2148.

    CAS  Google Scholar 

  40. Derijard B, Hibi M, Wu IH, et al. JNK1: A protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 1994; 76(6): 1025–1037.

    Article  CAS  PubMed  Google Scholar 

  41. Kyriakis JM, Banerjee P, Nikolakaki E, et al. The stress-activated protein kinase subfamily of c-Jun kinases. Nature 1994; 369: 156–560.

    Article  CAS  PubMed  Google Scholar 

  42. McGuire WP, Rowinsky EK, Rosenshein NB, et al. Taxol: A unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Inter Med 1989; 111(4): 273–279.

    CAS  Google Scholar 

  43. Raingeaud J, Gupta S, Rogers JS, et al. Pro-inflammatory cytokines and environmental stress cause p38 mitogen- activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem 1995; 270(13): 7420–7426.

    CAS  PubMed  Google Scholar 

  44. Kyriakis JM, Avruch J. Sounding the alarm: Protein kinase cascades activated by stress and inflammation. J Biol Chem 1996; 271: 24313–24316.

    CAS  PubMed  Google Scholar 

  45. Ohtsuka T, Buchsbaum D, Oliver P, Makhija S, Kimberly R, Zhou T. Synergistic induction of tumor cell apoptosis by death receptor antibody and chemotherapy agent through JNK/p38 and mitochondrial death pathway. Oncogene 2003; 22: 2034–2044.

    CAS  PubMed  Google Scholar 

  46. Lee MW, Park SC, Yang YG, et al. The involvement of reactive oxygen species (ROS) and p38mitogen-activated protein (MAP) kinase in TRAIL/Apo2L-induced apoptosis. FEBS Letters 2002; 512: 313–318.

    CAS  PubMed  Google Scholar 

  47. Han J, Lee JD, Jiang Y, Li Z, Feng L, Ulevitch RJ. Characterization of the structure and function of a novel MAP kinase kinase (MKK6). J Biol Chem 1996; 271: 2886–2891.

    CAS  PubMed  Google Scholar 

  48. Enslen H, Raingeaud J, Davis RJ. Selective activation of p38 mitogen- activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. J Biol Chem 1998; 273: 1741–1748.

    Article  CAS  PubMed  Google Scholar 

  49. Kumar S, McDonnell PC, Gum RJ, Hand AT, Lee JC, Young PR. Novel homologues of CSBP/p38 MAP kinase: activation, substrate specificity and sensitivity to inhibition by pyridinyl imidazoles. Biochem Biophys Res Commun 1997; 235: 533–538.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Pharmacology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA

    T. Abdollahi, N. M. Robertson & G. Litwack

  2. Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA

    A. Abdollahi

  3. Jefferson Medical College, 604 S. Washington square 3112, Philadelphia, PA, 19106, USA

    T. Abdollahi

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  1. T. Abdollahi
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  2. N. M. Robertson
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  3. A. Abdollahi
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  4. G. Litwack
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Correspondence to T. Abdollahi.

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Abdollahi, T., Robertson, N.M., Abdollahi, A. et al. Inhibition of TRAIL-induced apoptosis by IL-8 is mediated by the p38-MAPK pathway in OVCAR3 cells. Apoptosis 10, 1383–1393 (2005). https://doi.org/10.1007/s10495-005-2139-x

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  • DOI: https://doi.org/10.1007/s10495-005-2139-x

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