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alpha-Interferon potentiates epidermal growth factor receptor-mediated effects on human epidermoid carcinoma KB cells
M Caraglia1, A Leardi, S Corradino
1Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università Federico II di Napoli, Italy.
Abstract:
The molecular mechanisms underlying the growth inhibition of human tumor cells induced by recombinant interferon-alpha (IFN alpha) are mostly unknown. It has been proposed that this effect could be related to down-regulation and/or impaired function of peptide growth factor receptors (PGF-Rs) in tumor cells exposed to IFN alpha. However, we have previously described that IFN alpha-induced growth inhibition of human epidermoid carcinoma cells is paralleled by up-regulation of epidermal growth factor receptor (EGF-R). Here we report that an increase in EGF-R synthesis is detectable after 3 hr of exposure to cytostatic concentration of IFN alpha in epidermoid KB tumor cells. In these experimental conditions IFN alpha does not depress and even potentiates EGF-R function. IFN alpha-treated KB cells retain sensitivity to the cytotoxic activity of the anti-EGF-R 225 monoclonal antibody (MAb), which acts through receptor blockade, and are sensitized to the growth-promoting effect of EGF. EGF-induced tyrosine (tyr) phosphorylation both of total cellular protein extracts and of the immunoprecipitated EGF-R is increased in IFN alpha-treated cells. We conclude that a cross-talk between IFN alpha and EGF occurs in KB cells since IFN alpha, at cytostatic concentration, potentiates the effects mediated by the EGF-R.
Insights
Recombinant interferon-alpha (IFN alpha) up-regulates epidermal growth factor receptor (EGF-R) synthesis and potentiates its function in human tumor cells. This suggests a cross-talk mechanism where IFN alpha enhances EGF-R-mediated effects.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- The mechanisms of tumor cell growth inhibition by interferon-alpha (IFN alpha) are not fully understood.
- Previous studies suggested impaired peptide growth factor receptor (PGF-R) function, but IFN alpha paradoxically up-regulated epidermal growth factor receptor (EGF-R) in some tumor cells.
Purpose of the Study:
- To investigate the molecular mechanisms of IFN alpha-induced growth inhibition in human tumor cells.
- To elucidate the relationship between IFN alpha treatment and epidermal growth factor receptor (EGF-R) expression and function.
Main Methods:
- Exposure of epidermoid KB tumor cells to cytostatic concentrations of IFN alpha.
- Analysis of EGF-R synthesis and function using Western blotting and immunoprecipitation.
- Assessment of cell sensitivity to anti-EGF-R monoclonal antibody (MAb) and epidermal growth factor (EGF).
Main Results:
- IFN alpha treatment led to increased EGF-R synthesis within 3 hours in KB cells.
- IFN alpha potentiated EGF-R function, evidenced by increased EGF-induced tyrosine phosphorylation.
- IFN alpha-treated cells remained sensitive to anti-EGF-R MAb and showed enhanced responses to EGF.
Conclusions:
- A cross-talk exists between IFN alpha and EGF signaling pathways in KB cells.
- IFN alpha, at cytostatic concentrations, enhances the functional effects mediated by EGF-R, contributing to tumor cell modulation.