Abstract
BackgroundDespite IFNα has been used extensively in the treatment of multiple myeloma (MM), there are also several reports suggesting that IFNα may aggravate isease in some MM patients. That means the effect of IFNα on the growth of myeloma cells in vivo may be different. In this study, we selected two human myeloma cell lines that vary remarkably in response to IFNα and focused on elucidating the mechanism of differential IFNα responsiveness.ResultsSko-007 is a myeloma cell line whose growth is arrested by IFNα; however, IFNα promoted the proliferation of the other myeloma cell line U266. We observed that the growth-stimulation effect of IFNα on U266 cells did not result from up-regulation of the IL-6 receptors on cell surface; while IFNα treatment on Sko-007 cells significantly reduced gp130 expression. Moreover, the transcription factors STAT3 and STAT1, which are involved in the JAK/STAT signal transduction pathway, can be activated in both IFNα-stimulated and -inhibited myeloma cell lines; while the activation of the protein kinase ERK, which is involved in the Ras/MAPK signal transduction pathway, can be down-regulated in IFNα-arrested Sko-007 cells and up-regulated in IFNα-stimulated U266 cells. In addition, both IFNα-induced growth-stimulation effect and the up-regulated activation of ERK in U266 cells were efficiently inhibited by PD98059, the specific inhibitor of MAPK/ERK kinase (MEK).ConclusionMyeloma cells responsiveness to IFNα is heterogeneous and the activation state of ERK in the Ras/MAPK signalling pathway mainly contributed to this difference.
Highlights
Despite IFNα has been used extensively in the treatment of multiple myeloma (MM), there are several reports suggesting that IFNα may aggravate isease in some MM patients
A considerable number of the clinical trials have addressed the effectiveness of IFNα on MM therapy [2], other reports showed that in some MM patients, IFNα can promote the proliferation of myeloma cells in vivo and result in the development of aggressive plasma cell leukemia (PCL) [3]
Myeloma cell lines are heterogeneous in response to IFNα To determine the effect of IFNα on the growth of myeloma cells, MTT assay was firstly performed on four human myeloma cell lines-Sko-007, U266, KM-3 and XG-7 [7]
Summary
Despite IFNα has been used extensively in the treatment of multiple myeloma (MM), there are several reports suggesting that IFNα may aggravate isease in some MM patients. That means the effect of IFNα on the growth of myeloma cells in vivo may be different. We selected two human myeloma cell lines that vary remarkably in response to IFNα and focused on elucidating the mechanism of differential IFNα responsiveness. We have investigated in detail the mechanism of IL-6 signal transduction in different human myeloma cell lines [6]. We analyzed IFNα-induced activation of STAT3, STAT1 and ERK in Sko-007 and U266 human myeloma cell lines, which displayed overall different response to IFNα. We demonstrated the evidence that the activation state of the Ras/MAPK in stead of the JAK/STAT signal transduction pathway accounted mainly for the differential effect of IFNα on myeloma cells
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