α‐interferon potentiates epidermal growth factor receptor‐mediated effects on human epidermoid carcinoma KB cells

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.

Interferon-α induces apoptosis in human KB cells through a stress-dependent mitogen activated protein kinase pathway that is antagonized by epidermal growth factor

“…We have previously reported that the treatment with 1000 IU/ml IFNa for 48 h induces 50% growth inhibition and EGF-R upregulation on KB cells. 5 We have found that, at these experimental conditions, 40% of IFNa-treated KB cells were apoptotic as demonstrated by internucleosomic DNA fragmentation and quantitized by FACS analysis after nuclear dye with propidium iodide ( Figure 1C, F and G). Apoptosis induction was further demonstrated by TUNEL technique ( Figure 2B).…”

“…2 ± 4 We have also demonstrated that the proliferative response of human epidermoid cancer KB cells to EGF is increased by IFNa. 5 This latter effect is paralleled by an increased tyrosine phosphorylation of cellular proteins and of the EGF-R itself in KB cells exposed to IFNa; 5 it is suggested that the EGF-R signalling is upregulated in IFNatreated tumour cells. 5 We have speculated that the enhanced expression and function of EGF-R by the tumour cells could represent a stress response that might be activated as an attempt to provide an escape mechanism to the growth inhibition induced by IFNa.…”

“…5 This latter effect is paralleled by an increased tyrosine phosphorylation of cellular proteins and of the EGF-R itself in KB cells exposed to IFNa; 5 it is suggested that the EGF-R signalling is upregulated in IFNatreated tumour cells. 5 We have speculated that the enhanced expression and function of EGF-R by the tumour cells could represent a stress response that might be activated as an attempt to provide an escape mechanism to the growth inhibition induced by IFNa. 6 Moreover, it is reported that IFNa induces apoptosis on human squamous cancer, 7 glioma 8 and virus-infected cells.…”

8-Cl-cAMP antagonizes mitogen-activated protein kinase activation and cell growth stimulation induced by epidermal growth factor

“…EGF-R up-regulation has also been reported after tumour cell treatment with low doses of adriamycin or retinoic acid (Jetten, 1980;Zuckier and Tritton, 1983). Furthermore, IFN-α, but not ARA-C, potentiates the growth-promoting effect of EGF in KB cells while inducing EGF-R up-regulation (Caraglia et al, 1995). On this basis, we have hypothesized that up-regulation of growth factor receptors is a common event in growth-inhibited tumour cells and could represent a protective response towards the antiproliferative stimuli (Tagliaferri et al, 1994).…”

“…We have selected as experimental model the KB epidermoid carcinoma cell line that is responsive to the mitogenic stimulus induced by EGF (Aboud-Pirak et al, 1988;Caraglia et al, 1995) and is growth inhibited by 8-Cl-cAMP treatment. We have found that the growth-promoting activity of EGF on KB cells was completely abolished by 8-Cl-cAMP.…”