The interaction of insulin-like growth factors (IGF) with the IGF-I receptor promotes cell proliferation and survival. We examined the role of the IGF-I receptor as a possible direct inhibitor of apoptosis induced by the topoisomerase I inhibitor etoposide. When exposed to this agent, BALB/c 3T3 cells that constitutively overexpress the human IGF-I receptor (p6 cells) arrested in S phase and subsequently underwent apoptosis as determined by the appearance of a pre-G1 apoptotic peak when studied by flow cytometry and the characteristic internucleosomal fragmentation of DNA. The addition of IGF-I markedly inhibited etoposide-induced apoptosis in a concentration-dependent manner. IGF-I was not mitogenic in the presence of etoposide. IGF-I was less effective in preventing apoptosis in parental BALB/c 3T3 cells and had no effect on etoposide-induced cell killing of mouse embryo fibroblasts that have a targeted disruption of the IGF-I receptor gene. These results demonstrate an important role for the IGF-I receptor as an inhibitor of apoptosis, independent of its mitogenic actions.

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This work was supported by NIH Grants AA-07309, AA-0123, CA-53484, and ACS CB48.

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