Mechanisms by which energy restriction inhibits carcinogenesis.

Cancer that occurs at numerous organ sites, including the colon and breast, is inhibited by energy restriction, and the inhibition is proportional to the degree of restriction imposed. In an effort to identify the mechanism(s) by which energy restriction exerts this effect, a short term model system of experimentally induced mammary carcinogenesis was used. Given that carcinogenesis is known to involve a dysregulation to tissue size homeostasis in which cell proliferation and cell death are in dysequilibrium, we hypothesized that energy restriction exerts its effect by altering one or more aspects of cell cycle regulation. It was observed that energy restriction inhibited cell proliferation and increased cell death due to apoptosis. Thus attention was next focused on aspects of cell cycle regulation that might be affected by energy restriction. It was observed that the amount of p27 protein, one member of the Cip/Kip family of genes that are involved in cell cycle arrest, was increased dose dependently by energy restriction. Based on this and related observations, the hypothesis is advanced that energy restriction inhibits carcinogenesis, at least in part, by delaying cell cycle progression via shifting cell populations into a G(0)/G(1)state. Ongoing work indicates that corticosteroids, which are produced in increased amounts in response to energy restriction, may be involved in mediating this effect.