Dissociation between resistance to apoptosis and the transformed phenotypein IGF-I receptor signaling

Programmed Cell Death (PCD) is known to play an important role in both the development and the growth rate of human tumors. It has in fact been sugges ted that suppression of the apoptotic pathway is a requirement for the esta blishment of the transformed phenotype. In order to elucidate the relations hip between resistance to apoptosis and transformation, we have asked in th is investigation whether or not the two processes can be directly correlate d. For this purpose, we have used mouse embryo fibroblasts (MEF) expressing either the wild-type or several mutants of the type 1 insulin-like growth factor receptor (ICF-IR). The wild-type IGF-IR has both transforming and an ti-apoptotic activities, and we have asked whether these two activities can be or not separated in mutant receptors. Using this well-defined system, o ur results show that certain mutants of the IGF-IR that have strong anti-ap optotic and mitogenic activities, are incapable of transforming MEF (colony formation in soft agar). We have, instead, a good correlation between mito genic and anti-apoptotic activities, suggesting the possibility that the tw o processes may share similar signaling pathways from the IGF-IR. On the ot her hand, our results indicate that transformation requires an additional s ignal, above and beyond the mitogenic and survival signals. Our conclusion is that, at least in this system, the establishment of the malignant phenot ype and resistance to apoptosis can be dissociated, implying the possibilit y of separate targeting. J. Cell. Biochem. 72:294-310, 1999. (C) 1999 Wiley -Liss, Inc.