Abstract
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.
Keywords
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Article info
Publication history
Published online: February 17, 2009
Accepted:
January 13,
2009
Received:
September 18,
2008
Identification
Copyright
© 2009 Elsevier Ltd. Published by Elsevier Inc. All rights reserved.
