EGF activates an inducible survival response via the RAS-> Erk-1/2 pathway to counteract interferon-α-mediated apoptosis in epidermoid cancer cells

M. Caraglia, P. Tagliaferri, M. Marra, G. Giuberti, A. Budillon, E. Di Gennaro, S. Pepe, G. Vitale, S. Improta, P. Tassone, S. Venuta, A. R. Bianco, A. Abbruzzese

Research output: Contribution to journalArticle


The mechanisms of tumor cell resistance to interferon-α (IFNα) are at present mostly unsolved. We have previously demonstrated that IFNα induces apoptosis on epidermoid cancer cells and EGF antagonizes this effect. We have also found that IFNα-induced apoptosis depends upon activation of the NH2-terminal Jun kinase-1 (Jnk-1) and p38 mitogenactivated protein kinase, and that these effects are also antagonized by EGF. At the same time, IFNα increases the expression and function of the epidermal growth factor receptor (EGF-R). Here we report that the apoptosis induced by IFNα occurs together with activation of caspases 3, 6 and 8 and that EGF also antagonizes this effect. On the basis of these results, we have hypothesized that the increased EGF-R expression and function could represent an inducible survival response that might protect tumor cells from apoptosis caused by IFNα via extracellular signal regulated kinase 1 and 2 (Erk-1/2 cascades. We have found an increased activity of Ras and Raf-1 in IFNα-treated cells. Moreover, IFNα induces a 50% increase of the phosphorylated isoforms and enzymatic activity of Erk-1/2. We have also demonstrated that the inhibition of Ras activity induced by the transfection of the dominant negative Ras plasmid RASN17 and the inhibition of Mek-1 with PD098059 strongly potentiates the apoptosis induced by IFNα. Moreover, the selective inhibition of this pathway abrogates the counteracting effect of EGF on the IFNα-induced apoptosis. All these findings suggest that epidermoid tumor cells counteract the IFNα-induced apoptosis through a survival pathway that involves the hyperactivation of the EGF-dependent Ras->Erk signalling. The selective targeting of this pathway appears to be a promising approach in order to enhance the antitumor activity of IFNα.

Original languageEnglish
Pages (from-to)218-229
Number of pages12
JournalCell Death and Differentiation
Issue number2
Publication statusPublished - Feb 1 2003



  • Caspases
  • Dominant negative Ras
  • Epidermal growth factor receptor
  • Mek-1 inhibitor
  • New anticancer strategies

ASJC Scopus subject areas

  • Cell Biology

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