INSULIN-LIKE GROWTH-FACTOR-I (IGF-I) AND THE IGF-I RECEPTOR PREVENT ETOPOSIDE-INDUCED APOPTOSIS

The interaction of insulin-like growth factors (IGF) with the IGF-I re ceptor promotes cell proliferation and survival. We examined the role of the IGF-I receptor as a possible direct inhibitor of apoptosis indu ced by the topoisomerase I inhibitor etoposide. When exposed to this a gent, BALB/c 3T3 cells that constitutively overexpress the human IGF-I receptor (p6 cells) arrested in S phase and subsequently underwent ap optosis as determined by the appearance of a pre-G(1) apoptotic peak w hen studied by now cytometry and the characteristic internucleosomal f ragmentation of DNA. The addition of IGF-I markedly inhibited etoposid e-induced apoptosis in a concentration-dependent manner. IGF-I was not mitogenic in the presence of etoposide. IGF-I was less effective in p reventing apoptosis in parental BALB/c 3T3 cells and had no effect on etoposide-induced tell killing of mouse embryo fibroblasts that have a targeted disruption of the IGF-I receptor gene. These results demonst rate an important role for the IGF-I receptor as an inhibitor of apopt osis, independent of its mitogenic actions.