Modulation of growth and epidermal growth factor receptor activity by retinoic acid in human glioma cells

Abstract

The growth-inhibitory activity of beta-all-trans-retinoic acid (RA) was examined on seven cultured human gliomas and cells derived from one normal brain. Response in monolayer cultures was heterogenous: three cell lines were completely resistant whereas five cell lines were growth inhibited with 50% inhibitory dose ranging from greater than 10(-5) to 1 x 10(-8) M. Two glioma cell lines capable of forming colonies in soft agar exhibited dose-dependent sensitivity to RA-induced growth inhibition, whereas another cell line was not affected by RA under either growth condition. Cell cycle analysis of the glial-derived cells has shown that the RA-sensitive cells accumulated in the G0-G1 phase. The cell surface expression of epidermal growth factor (EGF) receptors displayed by the various cells was either slightly increased or not affected by RA. In addition, the affinity of binding was slightly decreased in some sensitive cells. The activity of EGF receptor as assessed by immunocomplex-kinase assays revealed a dose-dependent decrease in autophosphorylation activity that appeared to correlate with the growth inhibition. The decrease in phosphokinase activity represented a dose-dependent inhibition of phosphorylation on tyrosine residues on EGF receptor as well as several other substrates. Furthermore, the autophosphorylation of either RA-treated or untreated EGF receptors occurred on similar amino acid residues. These results demonstrate that RA exhibits a heterogeneous growth-inhibitory activity against human glioma cells and suggest that the effects of RA may be mediated, at least in part, by modulation of EGF receptor phosphotyrosine kinase activity.