Resistance to growth inhibition by transforming growth factor-beta in malignant glioma cells with functional receptors.

Abstract

The aim of this study was to investigate the mechanism by which malignant glioma cells escape from growth inhibition mediated by transforming growth factor-beta (TGF-beta), a ubiquitous cytokine that inhibits cell proliferation by causing growth arrest in the G1 phase of the cell cycle. The authors measured the response of eight malignant glioma cell lines to the growth-inhibiting activity of TGF-beta in vitro and the expression of TGF-beta Types I and II receptors in malignant glioma cells. The effect of TGF-beta on the expression of a p27Kip1 cyclin-dependent kinase inhibitor was also investigated to assess the downstream signal transmission from TGF-beta receptors. All malignant glioma cell lines were insensitive to growth inhibition by TGF-beta1 and TGF-beta2. Analyses of TGF-beta receptors by means of affinity labeling in which 125I-TGF-beta1 was used showed that six glioma lines had both TGF-beta Types I and II receptors on their cell surfaces, whereas two lines had very small amounts of TGF-beta Type I and/or Type II receptors. Northern blot analysis showed that all tumor lines expressed variable levels of messenger RNAs for both TGF-beta Types I and II receptors. Flow cytometric analyses revealed that treatment of malignant glioma cells with TGF-beta1 significantly downregulated the expression of p27Kip1 protein in all malignant glioma cell lines except one. The authors suggest that most malignant glioma cells express TGF-beta Types I and II receptors, which can transmit some signals downstream and that the loss of response to TGF-beta growth inhibition may not be caused by an abnormality of the TGF-beta receptors.