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-γ (IFN-γ)/signal transducer and activator of transcription 1 (STAT1) pathway because of the IGF-1-dependent internalization of the IFN-γR2 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-γR2 internalization and induces its cell surface accumulation in malignant T cells. This allows the reinstatement of the IFN-γ-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-γ administration could be a promising approach to suppress the growth of neoplastic T cells resistant to each treatment on its own.
| Original language | English |
|---|---|
| Pages (from-to) | 2496-2504 |
| Number of pages | 9 |
| Journal | Blood |
| Volume | 109 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Mar 15 2007 |
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ASJC Scopus subject areas
- Hematology
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In the absence of IGF-1 signaling, IFN-γ suppresses human malignant T-cell growth. / Conti, Laura; Regis, Gabriella; Longo, Angela; Bernabei, Paola; Chiarle, Roberto; Giovarelli, Mirella; Novelli, Francesco.
In: Blood, Vol. 109, No. 6, 15.03.2007, p. 2496-2504.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - In the absence of IGF-1 signaling, IFN-γ suppresses human malignant T-cell growth
AU - Conti, Laura
AU - Regis, Gabriella
AU - Longo, Angela
AU - Bernabei, Paola
AU - Chiarle, Roberto
AU - Giovarelli, Mirella
AU - Novelli, Francesco
PY - 2007/3/15
Y1 - 2007/3/15
N2 - 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-γ (IFN-γ)/signal transducer and activator of transcription 1 (STAT1) pathway because of the IGF-1-dependent internalization of the IFN-γR2 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-γR2 internalization and induces its cell surface accumulation in malignant T cells. This allows the reinstatement of the IFN-γ-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-γ administration could be a promising approach to suppress the growth of neoplastic T cells resistant to each treatment on its own.
AB - 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-γ (IFN-γ)/signal transducer and activator of transcription 1 (STAT1) pathway because of the IGF-1-dependent internalization of the IFN-γR2 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-γR2 internalization and induces its cell surface accumulation in malignant T cells. This allows the reinstatement of the IFN-γ-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-γ administration could be a promising approach to suppress the growth of neoplastic T cells resistant to each treatment on its own.
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U2 - 10.1182/blood-2006-07-034231
DO - 10.1182/blood-2006-07-034231
M3 - Article
VL - 109
SP - 2496
EP - 2504
JO - Blood
JF - Blood
SN - 0006-4971
IS - 6
ER -