Interferon-alpha treatment may negatively influence disease progression in melanoma patients by hyperactivation of STAT3 protein.
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.
Humpoliková-Adámková
L
L
Department of Experimental Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic.
Kovařík
J
J
Department of Experimental Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic.
Dušek
L
L
Institute of Biostatistics and Analyses, Masaryk University, Kamenice 3, 625 00 Brno, Czech Republic.
Lauerová
L
L
Department of Experimental Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic.
Boudný
V
V
Department of Experimental Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic.
Fait
V
V
Department of Experimental Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic.
Fojtová
M
M
Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, 612 65 Brno, Czech Republic.
Krejčí
E
E
Department of Experimental Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic.
Kovařík
A
A
Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, 612 65 Brno, Czech Republic. Electronic address: kovarik@ibp.cz.
D000328:Adult; D000368:Aged; D015153:Blotting, Western / Q000379:methods; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000009:adverse effects*; D016898:Interferon-alpha / Q000009:adverse effects*; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D008875:Middle Aged; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000032:analysis / Q000378:metabolism*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D007155:Immunologic Factors; D016898:Interferon-alpha; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053633:Receptor, Interferon alpha-beta