Alpha-Interferon and Its Effects on Signalling Pathways Within Cells

Michele      Caraglia; Giovanni      Vitale; Monica      Marra; Alfredo      Budillon; Pierosandro      Tagliaferri; Alberto      Abbruzzese

Abstract

Interferon-α (IFNα) is a recombinant protein widely used in the therapy of several neoplasms such as myeloma, renal cell carcinoma, epidermoid cervical and head and neck tumours and melanoma. IFNα, the first cytokine to be produced by recombinant DNA technology, has emerged as an important regulator of cancer cell growth and differentiation, affecting cellular communication and signal transduction pathways. However, the way by which tumour cell growth is directly suppressed by IFNα is not well known. Wide evidence exists on the possibility that cancer cells undergo apoptosis after the exposure to the cytokine. Here we will review the consolidate Signal transducer and activator of transcription (STAT)-dependent mechanism of action of IFNα and the supposed mechanism of apoptosis induction by IFNα. We will discuss data obtained by us and others on the triggering of the stress-dependent kinase pathway and on the modulation of protein synthesis machinery induced by IFNα and their correlations with the apoptotic process. Until today, inconsistent data have been obtained regarding the clinical e ffectiveness of IFNα in the therapy of solid tumours. In fact, the benefit of IFNα treatment is limited to some neoplasms while others are completely or partially resistant. The mechanisms of tumour resistance to IFNα have been studied in vitro. The alteration of JAK- Signal transducer and activator of transcription components of the IFNα-induced signalling, can be indeed a mechanism of resistance to IFN and cross talks between IFNα and survival signals has been also described. However, we have recently described a reactive mechanism of protection of tumour cells from the apoptosis induced by IFNα dependent on the epidermal growth factor (EGF)-mediated Ras / extracellular signal regulated kinase (Erk) signalling. The involvement of the Ras- > Erk pathway in the protection of tumour cells from the apoptosis induced by IFNα is further demonstrated by both Ras inactivation by RASN17 transfection and mitogen extracellular signal regulated kinase 1 (Mek-1) inhibition by exposure to PD098059. These data strongly suggest that the specific disruption of the latter could be a useful approach to potentiate the antitumour activity of IFNα against human tumours based on the new mechanistic insights achieved in the last years.

Keywords: interferon, stat, socs, ubiquitin, egf-r, ras, eif5a, hypusine