Interferon-alpha treatment may negatively influence disease progression in melanoma patients by hyperactivation of STAT3 protein
| Autor: | Lauerová L, Ladislav Dušek, V. Fait, V. Boudný, Miloslava Fojtová, A. Kovařík, E. Krejci, L. Humpoliková-Adámková, J. Kovařík |
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| Rok vydání: | 2008 |
| Předmět: |
Adult
STAT3 Transcription Factor Cancer Research Skin Neoplasms medicine.medical_treatment Blotting Western Alpha interferon Kaplan-Meier Estimate Receptor Interferon alpha-beta Disease-Free Survival 03 medical and health sciences 0302 clinical medicine medicine Tumor Cells Cultured Humans Immunologic Factors RNA Messenger Phosphorylation Melanoma Interferon alfa 030304 developmental biology Aged Cell Proliferation 0303 health sciences Cytokine Therapy Dose-Response Relationship Drug business.industry Cancer Interferon-alpha Immunotherapy Middle Aged medicine.disease Immunohistochemistry 3. Good health Up-Regulation Cytokine Oncology Tumor progression 030220 oncology & carcinogenesis Lymphatic Metastasis Immunology Cancer research Disease Progression business medicine.drug |
| Zdroj: | European journal of cancer (Oxford, England : 1990). 45(7) |
| ISSN: | 1879-0852 |
| Popis: | Interferon-alpha (IFN-alpha) is an important drug used in anti-melanoma therapy. However, metastases eventually reappear in almost 60% of melanoma patients, who have received adjuvant cytokine therapy suggesting that IFN-alpha can paradoxically promote disease progression in some cases, at least. In this study, we have investigated the possibility that a growth-promoting STAT3 protein might be activated by interferon-alpha in melanoma cells. We examined 24 primary cultures established from node metastases of melanoma patients who were monitored in a 5-year clinical follow-up. The patients differed in the course of disease and survival end-points. Using Western blot analyses, we show that interferon-alpha stimulated STAT3 phosphorylation at tyrosine (Y705) residue in 17% of cases. These over-reactive cell populations originated from patients who had the shortest disease-free intervals. A significant correlation was obtained between the length of survival end-points and a lack of STAT3 activation by IFN-alpha. No STAT3 induction was observed in normal melanocytes. The STAT1 activation at tyrosine (Y701) occurred at a similar frequency as that of STAT3 (17%) albeit in different patients, no clear correlation with the clinical status could be made. The interferon-alpha/beta receptors (IRFARs) were expressed irrespective to the signal transducers and activators of transcription (STATs) inducibility suggesting that signalling defects occur downstream from IRFAR. We propose that in some cases the application of IFN-alpha could increase the probability of disease progression via overactive STAT3. The tests for STAT3 inducibility prior to cytokine immunotherapy in the clinic are therefore warranted. |
| Databáze: | OpenAIRE |
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