title: Type I interferon gene transfer sensitizes melanoma cells to apoptosis via a target activity on mitochondrial function.
abstract: Our previous article reported that retroviral transduction of human type I consensus interferon-coding sequence into two human melanoma cells increased their susceptibility to cisplatin-induced apoptosis. Importantly, primary melanoma cells were significantly more sensitive to cisplatin-induced apoptosis with respect to metastatic melanoma cells. The aim of this study was to elucidate the subcellular mechanisms involved in this interferon-induced apoptotic proneness. Our results indicate that 1) cisplatin-induced apoptosis can be referred to as the type II apoptosis, ie, to the mitochondrially driven cascade; 2) treatment of interferon-producing melanoma cells with other type II apoptotic stimuli, such as radiation or staurosporine, also resulted in massive apoptosis, whereas type I stimuli, ie, anti-Fas, were ineffective; 3) interferon sensitization involved the caspase cascade in primary melanoma cells and the alternative pathway represented by cathepsin-mediated apoptosis in metastatic melanoma cells; 4) interferon production sensitizes cells to apoptosis by inducing, as the earliest event, mitochondrial membrane hyperpolarization. These results suggest that constitutive production of type I interferon by melanoma cells can act as an intracellular booster capable of increasing cell proneness to apoptosis by specifically modifying mitochondrial homeostasis and independently from the apoptotic cascade involved.
authors.affiliation: Department of Ultrastructures, Istituto Superiore di Sanità, Rome Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Matarrese
authors.forename: Luigi
authors.initials: L
authors.lastname: Di Biase
authors.forename: Laura
authors.initials: L
authors.lastname: Santodonato
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Straface
authors.forename: Monica
authors.initials: M
authors.lastname: Mecchia
authors.forename: Barbara
authors.initials: B
authors.lastname: Ascione
authors.forename: Giorgio
authors.initials: G
authors.lastname: Parmiani
authors.forename: Filippo
authors.initials: F
authors.lastname: Belardelli
authors.forename: Maria
authors.initials: M
authors.lastname: Ferrantini
authors.forename: Walter
authors.initials: W
authors.lastname: Malorni
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D002945:Cisplatin / Q000494:pharmacology; D004351:Drug Resistance / Q000502:physiology; D018014:Gene Transfer Techniques; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000502:physiology*; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins; D007370:Interferon Type I; D017382:Reactive Oxygen Species; D025801:Ubiquitin; D002945:Cisplatin