Calorie restriction has been shown to inhibit epithelial
carcinogenesis and this method of
dietary restriction reduces many circulating
proteins, including
insulin-like growth factor I (
IGF-I). Previously, we identified a relationship between elevated tissue
IGF-I levels and enhanced susceptibility to chemically induced skin
tumorigenesis. In this study, liver
IGF-I-deficient (LID) mice, which have a 75% reduction in serum
IGF-I, were subjected to the standard two-stage skin
carcinogenesis protocol using
7,12-dimethylbenz(a)anthracene as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. We observed a significant reduction in epidermal thickness and labeling index in LID mice treated with either vehicle or TPA. A significant decrease in both
tumor incidence and
tumor multiplicity was observed in LID mice undergoing two-stage skin
carcinogenesis relative to wild-type littermates. Western blot analyses of epidermal extracts revealed reduced activation of both the
epidermal growth factor and
IGF-I receptors in response to TPA treatment in LID mice. In addition, reduced activation of both Akt and the
mammalian target of rapamycin (mTOR) was observed in LID mice following TPA treatment relative to wild-type controls. Signaling downstream of mTOR was also reduced. These data suggest a possible mechanism whereby reduced circulating
IGF-I leads to attenuated activation of the Akt and mTOR signaling pathways, and thus, diminished epidermal response to
tumor promotion, and ultimately, two-stage skin
carcinogenesis. The current data also suggest that reduced circulating
IGF-I levels which occur as a result of calorie restriction may lead to the inhibition of skin
tumorigenesis, at least in part, by a similar mechanism.