科研之友
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摘要
Object. Malignant glioma cells secrete and activate transforming growth factor-beta (TGF beta) and are resistant to growth inhibition by that factor. Nevertheless, the mechanism underlying this effect remains poorly understood. In this study, the mechanism of the resistance to growth inhibition induced by TGF beta was investigated. Methods. The authors examined the expression of downstream components of the TGF beta receptor, including Smad2, Smad3, Smad4, and Smad7, and the effect of TGF beta(1) treatment on the phosphorylation of Smad2 and the nuclear translocation of Smad2 and Smad3 by using 10 glioma cell lines and the A549 cell line, which is sensitive to TGF beta-mediated growth inhibition. The expression of two transcriptional corepressor proteins, SnoN and Ski, and the effect of TGF beta(1) treatment on the expression of the SnoN protein and the cell cycle regulators p21, p15, cyclin-dependent kinase-4 (CDK4), and cyclin D1 were also examined. Expression of the Smad2 and Smad3 proteins was lower in the glioma cell lines than in the A549 cell line and in normal astrocytes. In particular, Smad3 expression was low or very low in nine of the 10 malignant glioma cell lines. Expression of Smad4 was low in four glioma cell lines, and expression of the Smad7 protein was similar when compared with protein expression in the A549 cell line and in normal astrocytes. The levels of Smad2 phosphorylation after TGF beta(1) treatment were lower in glioma cell lines than in the A549 cell line, except for one glioma cell line. Seven of the 10 glioma cell lines exhibited lower levels of nuclear translocation of Smad2 and Smad3, and two cell lines that expressed very low levels of Smad3 protein showed no nuclear translocation. All glioma cell lines expressed the SnoN protein and its expression was unaltered by treatment with TGF beta(1). Three glioma cell lines expressed high levels of the Ski protein. The expression of the p21(cipl), p15(INK4B), CDK4, and cyclin D1 proteins was not altered by. TGF beta(1) treatment, except in one cell line that displayed a slight increase in p21 protein. Overall, the expression of the Smad2 and Smad3 proteins was low in the glioma cell lines, the phosphorylation and nuclear translocation of Smad2 and Smad3 were impaired, and the TGF beta receptor signal did not affect the expression of the SnoN, p21, p15, cyclin D1, and CDK4 proteins. Conclusions. These results suggest that the ability to resist TGF beta-mediated growth inhibition in malignant glioma cells is due to abnormalities in the TGF beta signaling pathway.
- 出版日期2006-7
