In the absence of IGF-1 signaling, IFN-gamma suppresses human malignant T-cell growth.
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.
Conti
Laura
L
Center for Experimental Research and Medical Studies (CERMS), San Giovanni Battista Hospital, Turin, Italy.
Regis
Gabriella
G
Longo
Angela
A
Bernabei
Paola
P
Chiarle
Roberto
R
Giovarelli
Mirella
M
Novelli
Francesco
F
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*
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