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Inhibition of epidermal growth factor receptor activity by retinoic acid in glioma cells
1Department of Neuro-Oncology, M. D. Anderson Cancer Center, University of Texas, Houston 77030.
Abstract:
The growth inhibitory effects of exogenously added retinoic acid (RA) on various cultured human glioma cells was observed to be heterogenous, with an ID50 ranging from 10(-7) M to no response. The protein tyrosine kinase activity of epidermal growth factor receptor (EGF-receptor) appeared to parallel the cell's growth responsiveness to RA. Cells sensitive to RA-induced growth inhibition exhibited a dose-dependent decrease in EGF-receptor activity, whereas RA-resistant cells showed no alterations in EGF-receptor protein tyrosine kinase activity or expression. The modulation of EGF-receptor by RA was further examined with RA-sensitive (LG) and -resistant (NG-1) cell lines. Both cell lines were approximately equal in their ability to bind and internalize epidermal growth factor in the presence or absence of RA. Several independent assays suggested that the inhibition of EGF-receptor activity was independent of protein kinase C modulation as mediated by phorbol myristate acetate. However, alterations in associated glycoconjugates of EGF-receptor were observed among the sensitive cells but not the resistant cells. These results suggest RA-induced growth inhibition in sensitive cells may arise, at least in part, through alterations in EGF-receptor and structure.
Insights
Retinoic acid (RA) shows varied growth inhibition in human glioma cells. Sensitive cells experience reduced epidermal growth factor (EGF)-receptor activity, suggesting a link between RA
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- Retinoic acid (RA) is a derivative of vitamin A with known roles in cell differentiation and growth.
- Glioma, a type of brain tumor, exhibits heterogeneous responses to therapeutic agents.
- Epidermal growth factor receptor (EGF-receptor) signaling is frequently dysregulated in cancers, including gliomas.
Purpose of the Study:
- To investigate the heterogeneous growth inhibitory effects of retinoic acid (RA) on human glioma cells.
- To determine the relationship between cellular response to RA and epidermal growth factor (EGF)-receptor activity.
- To elucidate the molecular mechanisms underlying RA-induced growth inhibition in sensitive glioma cells.
Main Methods:
- Cultured human glioma cells were treated with varying concentrations of retinoic acid (RA).
- Cell growth inhibition was assessed, and epidermal growth factor (EGF)-receptor protein tyrosine kinase activity was measured.
- Specific assays were used to examine EGF-receptor modulation, including binding, internalization, and associated glycoconjugates, in RA-sensitive and RA-resistant cell lines.
Main Results:
- Glioma cell sensitivity to RA's growth inhibitory effects varied significantly.
- RA-sensitive cells showed a dose-dependent decrease in EGF-receptor activity, while resistant cells did not.
- Alterations in EGF-receptor-associated glycoconjugates were observed in RA-sensitive cells but not in resistant cells, independent of protein kinase C modulation.
Conclusions:
- The heterogeneous response of glioma cells to RA is linked to modulation of EGF-receptor activity.
- RA-induced growth inhibition in sensitive glioma cells may involve alterations in EGF-receptor activity and structure.
- These findings suggest a potential therapeutic strategy targeting EGF-receptor signaling in conjunction with RA for glioma treatment.