title: In the absence of IGF-1 signaling, IFN-gamma suppresses human malignant T-cell growth.
abstract: Several approaches to target insulin-like growth factor-1 (IGF-1) signaling have resulted in the inhibition of the growth of a broad range of tumor cells. Malignant T cells are insensitive to the antiproliferative effects of the interferon-gamma (IFN-gamma)/signal transducer and activator of transcription 1 (STAT1) pathway because of the IGF-1-dependent internalization of the IFN-gammaR2 signaling chain. Here we show that human malignant T cells are also resistant to the growth inhibitory effect of both the IGF-1 receptor-specific inhibitor picropodophyllin (PPP) and retrovirus-mediated gene transfer of a dominant negative IGF-1 receptor. However, blockade of IGF-1 receptor perturbs IFN-gammaR2 internalization and induces its cell surface accumulation in malignant T cells. This allows the reinstatement of the IFN-gamma-induced STAT1 activation, a high expression of proapoptotic molecules, and the suppression of malignant T-cell growth both in vitro and in vivo in a severe combined immunodeficiency (SCID) mouse model. These data indicate that the inhibition of IGF-1 signaling combined with IFN-gamma administration could be a promising approach to suppress the growth of neoplastic T cells resistant to each treatment on its own.
authors.affiliation: Center for Experimental Research and Medical Studies (CERMS), San Giovanni Battista Hospital, Turin, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Conti
authors.forename: Gabriella
authors.initials: G
authors.lastname: Regis
authors.forename: Angela
authors.initials: A
authors.lastname: Longo
authors.forename: Paola
authors.initials: P
authors.lastname: Bernabei
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiarle
authors.forename: Mirella
authors.initials: M
authors.lastname: Giovarelli
authors.forename: Francesco
authors.initials: F
authors.lastname: Novelli
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism*; D015458:Leukemia, T-Cell / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D017471:Receptors, Interferon / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C120411:interferon receptor, type II; C415032:picropodophyllin; D007334:Insulin-Like Growth Factor I; D007371:Interferon-gamma; D017526:Receptor, IGF Type 1; D011034:Podophyllotoxin