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Impact of IFNα2b upon pSTAT3 and the MEK/ERK MAPK Pathway in Melanoma

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Abstract

Purpose

High-dose IFNα2b (HDI) was established as the first effective adjuvant therapy for patients with high-risk resected melanoma more than a decade ago, but its fundamental molecular mechanism of action remains unclear. STAT3 and the mitogen activated protein kinases (MAPKs), especially ERK (extracellular signal-regulating kinase) and MEK (MAPK/ERK kinase), play roles in melanoma progression and host immunity. We have therefore evaluated STAT3 and MEK/ERK MAP kinases in patients with regional lymph node metastasis (stage IIIB) of melanoma in the context of a prospective neoadjuvant trial of HDI (UPCI 00-008).

Patients and methods

In the context of this trial, HDI was administered daily for 20 doses following diagnostic biopsy, and prior to definitive surgery. Immunohistochemistry for pSTAT3, phospho-MEK1/2, phospho-ERK1/2, and EGFR was performed on paired fixed (nine patients) biopsies.

Results

HDI was found to down-regulate pSTAT3 (P = 0.008) and phospho-MEK1/2 (P = 0.008) levels significantly in tumor cells. Phospho-ERK1/2 was down-regulated by HDI in tumor cells (P = 0.015), but not in lymphoid cells. HDI down-regulated EGFR (P = 0.013), but pSTAT3 activation appeared not to be associated with EGFR expression and the MEK/ERK MAPK pathway.

Conclusion

We conclude that HDI regulates MAPK signaling differentially in melanoma tumor cells and host lymphoid cells in vivo. STAT3 activation is independent of the EGFR/MEK/ERK signaling pathway.

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References

  1. Adachi S, Iwata M (2002) Duration of calcineurin and Erk signals regulates CD4/CD8 lineage commitment of thymocytes. Cell Immunol 215:45–53

    Article  PubMed  CAS  Google Scholar 

  2. Chatterjee M, Stuhmer T, Herrmann P, Bommert K, Dorken B, Bargou RC (2004) Combined disruption of both the MEK/ERK and the IL-6R/STAT3 pathways is required to induce apoptosis of multiple myeloma cells in the presence of bone marrow stromal cells. Blood 104:3712–3721

    Article  PubMed  CAS  Google Scholar 

  3. Coppo P, Flamant S, De Mas V, Jarrier P, Guillier M, Bonnet ML, Lacout C, Guilhot F, Vainchenker W, Turhan AG (2006) BCR-ABL activates STAT3 via JAK and MEK pathways in human cells. Br J Haematol 134:171–179

    Article  PubMed  CAS  Google Scholar 

  4. Cowley S, Paterson H, Kemp P, Marshall CJ (1994) Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77:841–852

    Article  PubMed  CAS  Google Scholar 

  5. Djeu JY, Jiang K, Wei S (2002) A view to a kill: signals triggering cytotoxicity. Clin Cancer Res 8:636–640

    PubMed  CAS  Google Scholar 

  6. Frank DA (2007) STAT3 as a central mediator of neoplastic cellular transformation. Cancer Lett 251:199–210

    Article  PubMed  CAS  Google Scholar 

  7. Gamero AM, Young HA, Wiltrout RH (2004) Inactivation of Stat3 in tumor cells: releasing a brake on immune responses against cancer? Cancer Cell 5:111–112

    Article  PubMed  CAS  Google Scholar 

  8. Gao SP, Bromberg JF (2006) Touched and moved by STAT3. Sci STKE 2006: pe30

  9. Gollob JA, Wilhelm S, Carter C, Kelley SL (2006) Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol 33:392–406

    Article  PubMed  CAS  Google Scholar 

  10. Haura EB, Turkson J, Jove R (2005) Mechanisms of disease: insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Pract Oncol 2:315–324

    Article  PubMed  CAS  Google Scholar 

  11. Hill CS, Treisman R (1995) Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell 80:199–211

    Article  PubMed  CAS  Google Scholar 

  12. Homsi J, Cubitt C, Daud A (2007) The Src signaling pathway: a potential target in melanoma and other malignancies. Expert Opin Ther Targets 11:91–100

    Article  PubMed  CAS  Google Scholar 

  13. Hunter T (1995) Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell 80:225–36

    Article  PubMed  CAS  Google Scholar 

  14. Inamura K, Matsuzaki Y, Uematsu N, Honda A, Tanaka N, Uchida K (2005) Rapid inhibition of MAPK signaling and anti-proliferation effect via JAK/STAT signaling by interferon-alpha in hepatocellular carcinoma cell lines. Biochim Biophys Acta 1745:401–410

    Article  PubMed  CAS  Google Scholar 

  15. Itoh M, Murata T, Suzuki T, Shindoh M, Nakajima K, Imai K, Yoshida K (2006) Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells. Oncogene 25:1195–1204

    Article  PubMed  CAS  Google Scholar 

  16. Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, Beug H, Grunert S (2002) Ras and TGF[beta. cooperatively regulate epithelial cell plasticity and metastasis dissection of Ras signaling pathways. J Cell Biol 156:299–313

    Article  PubMed  CAS  Google Scholar 

  17. Kirkwood JM, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernstoff MS, Rao U (2001) High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol 19:2370–2380

    PubMed  CAS  Google Scholar 

  18. Kirkwood JM, Manola J, Ibrahim J, Sondak V, Ernstoff MS, Rao U (2004) A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res 10:1670–1677

    Article  PubMed  CAS  Google Scholar 

  19. Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH (1996) Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14:7–17

    PubMed  CAS  Google Scholar 

  20. Kortylewski M, Jove R, Yu H (2005) Targeting STAT3 affects melanoma on multiple fronts. Cancer Metastasis Rev 24:315–327

    Article  PubMed  CAS  Google Scholar 

  21. Lee CK, Smith E, Gimeno R, Gertner R, Levy DE (2000) STAT1 affects lymphocyte survival and proliferation partially independent of its role downstream of IFN-gamma. J Immunol 164:1286–1292

    PubMed  CAS  Google Scholar 

  22. Marshall CJ (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80:179–185

    Article  PubMed  CAS  Google Scholar 

  23. Moschos SJ, Edington HD, Land SR, Rao UN, Jukic D, Shipe-Spotloe J, Kirkwood JM (2006) Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. J Clin Oncol 24:3164–3171

    Article  PubMed  CAS  Google Scholar 

  24. Niu G, Bowman T, Huang M, Shivers S, Reintgen D, Daud A, Chang A, Kraker A, Jove R, Yu H (2002) Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene 21:7001–7010

    Article  PubMed  CAS  Google Scholar 

  25. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D, Heller R, Ellis LM, Karras J, Bromberg J, Pardoll D, Jove R, Yu H (2002) Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21:2000–2008

    Article  PubMed  CAS  Google Scholar 

  26. Park S, Yeung ML, Beach S, Shields JM, Yeung KC (2005) RKIP downregulates B-Raf kinase activity in melanoma cancer cells. Oncogene 24:3535–3540

    Article  PubMed  CAS  Google Scholar 

  27. Romerio F, Zella D (2002) MEK and ERK inhibitors enhance the anti-proliferative effect of interferon-alpha2b. Faseb J 16:1680–1682

    PubMed  CAS  Google Scholar 

  28. Song L, Turkson J, Karras JG, Jove R, Haura EB (2003) Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene 22:4150–4165

    Article  PubMed  CAS  Google Scholar 

  29. Soreide K, Janssen EA, Korner H, Baak JP (2006) Trypsin in colorectal cancer: molecular biological mechanisms of proliferation, invasion, and metastasis. J Pathol 209:147–156

    Article  PubMed  CAS  Google Scholar 

  30. Teague TK, Schaefer BC, Hildeman D, Bender J, Mitchell T, Kappler JW, Marrack P (2000) Activation-induced inhibition of interleukin 6-mediated T cell survival and signal transducer and activator of transcription 1 signaling. J Exp Med 191:915–926

    Article  PubMed  CAS  Google Scholar 

  31. Thomas NE (2006) BRAF somatic mutations in malignant melanoma and melanocytic naevi. Melanoma Res 16:97–103

    Article  PubMed  CAS  Google Scholar 

  32. Tibshirani Ea (1993) An introduction to the Boostrap. Chapman & Hall, New York

    Google Scholar 

  33. Vial E, Sahai E, Marshall CJ (2003) ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility. Cancer Cell 4:67–79

    Article  PubMed  CAS  Google Scholar 

  34. Wang W, Edington HD, Rao UN, Jukic DM, Land SR, Ferrone S, Kirkwood JM (2007) Modulation of Signal Transducers and Activators of Transcription 1 and 3 Signaling in Melanoma by High-Dose IFN{alpha}2b. Clin Cancer Res 13:1523–1531

    Article  PubMed  CAS  Google Scholar 

  35. Wang W, Edington H, Rao UN, Jukic D, Mascari R, Sander C, Ferrone S, Moschos S, Kirkwood JM (2005) Effects of neoadjuvant high-dose interferon (IFNα2b) upon STAT signaling, IFNαRβ, MHC and Tap expression in lymph node metastatic melanoma (UPCI 008). Proc AACR 2005 (Abstr. 6003)

  36. Wang W, Edington HD, Rao UN, Jukic D, Land S, Mascari R, Sander C, Kirkwood JM (2006) Impact of neoadjuvant high-dose IFNα2b (HDI) upon STAT and MEK/ERK MAPK pathways in lymph node metastatic melanoma. Proc AACR 2006 (Abstr. 6198)

  37. Wang W, Edington H, Rao UN, Jukic D, Wang H, Mascari R, Sander C, Kirkwood JM (2006) Dose-depended modulation of STAT signaling in the atypical/dysplastic nevus by exposure to interferon α. Proc AACR (Abstr. 5815)

  38. Webb CP, Van Aelst L, Wigler MH, Woude GF (1998) Signaling pathways in Ras-mediated tumorigenicity and metastasis. Proc Natl Acad Sci USA 95:8773–8778

    Article  PubMed  CAS  Google Scholar 

  39. Wu J, Luo H (2005) Recent advances on T-cell regulation by receptor tyrosine kinases. Curr Opin Hematol 12:292–297

    Article  PubMed  CAS  Google Scholar 

  40. Xie TX, Huang FJ, Aldape KD, Kang SH, Liu M, Gershenwald JE, Xie K, Sawaya R, Huang S (2006) Activation of stat3 in human melanoma promotes brain metastasis. Cancer Res 66:3188–3196

    Article  PubMed  CAS  Google Scholar 

  41. Yang J, Chatterjee-Kishore M, Staugaitis SM, Nguyen H, Schlessinger K, Levy DE, Stark GR (2005) Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation. Cancer Res 65:939–947

    PubMed  CAS  Google Scholar 

  42. Yu H, Jove R (2004) The STATs of cancer—new molecular targets come of age. Nat Rev Cancer 4:97–105

    Article  PubMed  CAS  Google Scholar 

  43. Zhang YL, Dong C (2005) MAP kinases in immune responses. Cell Mol Immunol 2:20–27

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research study was supported by the Grant Channel Memorial Fund of the University of Pittsburgh Cancer Institute’s Melanoma Program. We thank the generous support of the Grant Channel Memorial Fund of the UPCI Melanoma Program.

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Hillman Cancer Center, Research Pavilion, Suite 1.32, 5117 Centre Avenue, Pittsburgh, PA, 15213-2584, USA

    Wenjun Wang & John M. Kirkwood

  2. Department of Surgery, Magee Women’s Hospital, Pittsburgh, PA, USA

    Howard D. Edington

  3. Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Drazen M. Jukic

  4. Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Drazen M. Jukic & Uma N. M. Rao

  5. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Stephanie R. Land

  6. Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Research Pavilion, Suite 1.32, 5117 Centre Avenue, Pittsburgh, PA, 15213-2584, USA

    Wenjun Wang & John M. Kirkwood

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  1. Wenjun Wang
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  2. Howard D. Edington
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Correspondence to John M. Kirkwood.

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Wang, W., Edington, H.D., Jukic, D.M. et al. Impact of IFNα2b upon pSTAT3 and the MEK/ERK MAPK Pathway in Melanoma. Cancer Immunol Immunother 57, 1315–1321 (2008). https://doi.org/10.1007/s00262-008-0466-9

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  • DOI: https://doi.org/10.1007/s00262-008-0466-9

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