Visit our Expo - Redox and Inflammation signaling 2012

Session X : Cell death in cancer Poster X, 22
In the absence of Insulin-like Growth Factor (IGF)-1 signaling, Interferon-gamma (IFNg)
inhibits the growth of human malignant T cells
Laura Conti1,2, Angela Longo1, Gabriella Regis1,2, Mirella Giovarelli1,2, Roberto
Chiarle1 and Francesco Novelli1,2.
1Center for Experimental Research and Medical Studies (CERMS), San Giovanni
Battista Hospital-Molinette, via Santena 5, 10126 Turin, Italy, and 2Department of
Medicine and Experimental Oncology, Section of Pathology, University of Turin, C.so
Raffaello 30, 10125 Turin, Italy. E-mail: laura.conti@unito.it.
IGF-1 is a growth factor that promotes the survival and proliferation of many tumors and cell
types, and several approaches to target IGF-1 signaling have resulted in the induction of
apoptosis in a broad range of tumor cells. However, we have found that human malignant T
cells, which are insensitive to the antiproliferative and apoptotic effects of IFN-g, still grow in
the absence of IGF-1 signaling. T cell refractoriness to the IFN-g/Signal Transducer and
Activator of Transcription (STAT) 1 pathway mainly rests on internalization of the IFN-g
Receptor 2 (IFN-gR2) signaling chain, which is critically induced by IGF-1. Here we show
that retrovirus-mediated gene transfer of a dominant negative IGF-1 Receptor (IGF-1R DN)
inhibits IFN-gR2 internalization and induces its cell surface accumulation. This results in a
strong and sustained IFN-g-induced STAT1 activation and consequently in the high
expression of pro-apoptotic molecules that render malignant T cells susceptible to the
antiproliferative and apoptotic effects of IFN-g, both in vitro and in vivo. These data indicate
that inhibition of IGF-1 signaling associated with IFN-g administration could be a useful
approach to inhibit the growth of neoplastic T cells resistant to each treatment on its own.
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