Type I interferon gene transfer sensitizes melanoma cells to apoptosis via a target activity on mitochondrial function.
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.
Matarrese
Paola
P
Department of Ultrastructures, Istituto Superiore di Sanità, Rome Italy.
Di Biase
Luigi
L
Santodonato
Laura
L
Straface
Elisabetta
E
Mecchia
Monica
M
Ascione
Barbara
B
Parmiani
Giorgio
G
Belardelli
Filippo
F
Ferrantini
Maria
M
Malorni
Walter
W
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
D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins; D007370:Interferon Type I; D017382:Reactive Oxygen Species; D025801:Ubiquitin; D002945:Cisplatin