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 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.
Sell
C
C
Department of Pathology, Jefferson Medical College, Philadelphia, Pennsylvania 19107.
Baserga
R
R
Rubin
R
R
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D005047:Etoposide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D016196:S Phase
D007334:Insulin-Like Growth Factor I; D005047:Etoposide; D017526:Receptor, IGF Type 1