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Epidermal growth factor protects epithelial cells against Fas-induced apoptosis. Requirement for Akt activation
1Program in Molecular Signal Transduction, Division of Basic Sciences, National Jewish Medical and Research Center, University of Colorado Medical School, Denver, Colorado 80206, USA.
Abstract:
Chemotherapeutic drugs that damage DNA kill tumor cells, in part, by inducing the expression of a death receptor such as Fas or its ligand, FasL. Here, we demonstrate that epidermal growth factor (EGF) stimulation of T47D breast adenocarcinoma and embryonic kidney epithelial (HEK293) cells protects these cells from Fas-induced apoptosis. EGF stimulation of epithelial cells also inhibited Fas-induced caspase activation and the proteolysis of signaling proteins downstream of the EGF receptor, Cbl and Akt/protein kinase B (Akt). EGF stimulation of Akt kinase activity blocked Fas-induced apoptosis. Expression of activated Akt in MCF-7 breast adenocarcinoma cells was sufficient to block Fas-mediated apoptosis. Inhibition of EGF-stimulated extracellular signal-regulated kinase (ERK) activity did not affect EGF protection from Fas-mediated apoptosis. The findings indicate that EGF receptor stimulation of epithelial cells has a significant survival function against death receptor-induced apoptosis mediated by Akt.
Insights
Epidermal growth factor (EGF) protects epithelial cells from Fas-induced apoptosis by activating Akt kinase. This finding reveals a survival mechanism against death receptor-mediated cell death in cancer research.
Area of Science:
- Cell Biology
- Molecular Oncology
- Signal Transduction
Background:
- Chemotherapy induces tumor cell death via DNA damage, often involving death receptors like Fas.
- Epithelial cells are susceptible to apoptosis induced by death receptor signaling pathways.
Purpose of the Study:
- To investigate the role of epidermal growth factor (EGF) in modulating Fas-induced apoptosis in epithelial cells.
- To elucidate the downstream signaling pathways involved in EGF-mediated protection against apoptosis.
Main Methods:
- Stimulation of T47D and HEK293 epithelial cells with EGF.
- Assessment of Fas-induced apoptosis, caspase activation, and protein proteolysis.
- Analysis of Akt kinase activity and its role in apoptosis.
- Expression of activated Akt in MCF-7 cells.
Main Results:
- EGF stimulation protected T47D and HEK293 cells from Fas-induced apoptosis.
- EGF inhibited Fas-induced caspase activation and proteolysis of Cbl and Akt.
- EGF-stimulated Akt kinase activity was sufficient to block Fas-induced apoptosis.
- Extracellular signal-regulated kinase (ERK) pathway inhibition did not affect EGF-mediated protection.
Conclusions:
- EGF receptor stimulation confers a significant survival advantage to epithelial cells.
- Akt activation is a key mediator of EGF's protective effect against death receptor-induced apoptosis.
- These findings highlight a novel survival pathway relevant to cancer therapy and resistance.