Abstract
BackgroundS100A4 is a small Ca2+-binding protein of the S100 family with metastasis-promoting properties. Recently, secreted S100A4 protein has been shown to possess a number of functions, including induction of angiogenesis, stimulation of cell motility and neurite extension.MethodsCell cultures from two human osteosarcoma cell lines, OHS and its anti-S100A4 ribozyme transfected counterpart II-11b, was treated with IFN-γ and recombinant S100A4 in order to study the sensitizing effects of extracellular S100A4 on IFN-γ mediated apoptosis. Induction of apoptosis was demonstrated by DNA fragmentation, cleavage of poly (ADP-ribose) polymerase and Lamin B.ResultsIn the present work, we found that the S100A4-expressing human osteosarcoma cell line OHS was more sensitive to IFN-γ-mediated apoptosis than the II-11b cells. S100A4 protein was detected in conditioned medium from OHS cells, but not from II-11b cells, and addition of recombinant S100A4 to the cell medium sensitized II-11b cells to apoptosis induced by IFN-γ. The S100A4/IFN-γ-mediated induction of apoptosis was shown to be independent of caspase activation, but dependent on the formation of reactive oxygen species. Furthermore, addition of extracellular S100A4 was demonstrated to activate nuclear factor-κB (NF-κB).ConclusionIn conclusion, we have shown that S100A4 sensitizes osteosarcoma cells to IFN-γ-mediated induction of apoptosis. Additionally, extracellular S100A4 activates NF-κB, but whether these events are causally related remains unknown.
Highlights
S100A4 is a small Ca2+-binding protein of the S100 family with metastasis-promoting properties
Searching for cytokines and signal transduction modulators affecting S100A4 expression, we recently discovered that IFN-γ downregulated S100A4 transcription and induced apoptosis in the human osteosarcoma cell line OHS [24]
We show that S100A4 can be secreted from these human osteosarcoma cells, and that extracellular addition of recombinant S100A4 (rS100A4) sensitizes cells to apoptosis induced by IFN-γ
Summary
S100A4 is a small Ca2+-binding protein of the S100 family with metastasis-promoting properties. Secreted S100A4 protein has been shown to possess a number of functions, including induction of angiogenesis, stimulation of cell motility and neurite extension. The S100 protein family consists of at least 21 small, acidic, Ca2+-binding proteins with different expression patterns and apparently diverse functional and biological properties [1]. It has been reported that S100A4 can be secreted, and suggested extracellular functions include induction of angiogenesis [9], stimulation of cell motility [10], and stimulation of neurite outgrowth [11]. We have recently demonstrated nuclear localization of S100A4, and an association between nuclear expression and tumor stage in colorectal cancer [12], indicating other, yet undiscovered, functions of S100A4. S100A4 has been reported to interact with the tumor suppressor protein p53 and to modulate transcription of downstream target genes, influencing p53-mediated apoptosis [13]
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