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Reduced Susceptibility to Two-Stage Skin Carcinogenesis in Mice with Low Circulating Insulin-Like Growth Factor I Levels

¹ The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas; ² The University of Texas, Division of Nutritional Sciences, Austin, Texas; and ³ Mt. Sinai School of Medicine, Division of Endocrinology, Diabetes and Bone Disease, New York, New York

Requests for reprints: John DiGiovanni, Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, P.O. Box 389, Smithville, TX 78957. Phone: 512-237-9414; Fax: 512-237-2522; E-mail: jdigiova{at}mdanderson.org or Stephen Hursting, The University of Texas, Division of Nutritional Sciences, One University Station, Austin, TX 78712. Phone: 512-471-2809; Fax: 512-471-5630; E-mail: shursting{at}mail.utexas.edu.

Key Words: Akt/mTOR • epithelial carcinogenesis • IGF-I

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. [Cancer Res 2008;68(10):3680–8]