Submitted July 7, 2006
Accepted October 31, 2006
In the absence of IGF-1 signaling, IFN-
suppresses human malignant T cell growth
Laura Conti, Gabriella Regis, Angela Longo, Paola Bernabei, Roberto Chiarle, Mirella Giovarelli, and Francesco Novelli*
Center for Experimental Research & Medical Studies (CERMS), San Giovanni Battista Hospital, Turin, Italy
Dept of Medicine & Experimental Oncology, Section of Pathology, University of Turin, Turin, Italy
* Corresponding author; email: franco.novelli{at}unito.it.
Several approaches to target Insulin-like Growth Factor (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 (IFN)-
/Signal Transducer and Activator of Transcription (STAT) 1 pathway because of the IGF-1-dependent internalization of the IFN-R2 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-R2 internalization and induces its cell surface accumulation in malignant T cells. This allows the reinstatement of the IFN--induced STAT1 activation, a high expression of pro-apoptotic molecules and the suppression of malignant T cell growth both in vitro and in vivo in a SCID mouse model. These data indicate that the inhibition of IGF-1 signaling combined with IFN- administration could be a promising approach to suppress the growth of neoplastic T cells resistant to each treatment on its own.
