Impact of IFNalpha2b upon pSTAT3 and the MEK/ERK MAPK pathway in melanoma.
OBJECTIVE
High-dose IFNalpha2b (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).


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.


CONCLUSIONS
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.
Wang
Wenjun
W
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.
Edington
Howard D
HD
Jukic
Drazen M
DM
Rao
Uma N M
UN
Land
Stephanie R
SR
Kirkwood
John M
JM
D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000378:metabolism* / Q000627:therapeutic use*; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000378:metabolism*; D015233:Models, Statistical; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases