The beneficial effects of dietary restriction (DR) in a number of organisms include increased life span and protection against age-related diseases, including cancer; however, not all types of cancer respond to DR in the same way (see commentary by Brunet). To address this question, Kalaany and Sabatini introduced various human cancer cell lines into immunocompromised mice and monitored the effect of DR on both the incidence and size of the resulting tumors. They found that tumors could be classified into one of two types: those whose volume was reduced in mice subjected to DR compared to that in mice with a normal diet, and those that were resistant to the effects of DR. Because cell lines that generated DR-resistant tumors could grow in culture media devoid of insulin or insulin-like growth factor 1 (IGF1), whereas DR-sensitive cell lines could not, the authors investigated phosphoinositide 3-kinase (PI3K) and Akt, components of insulin and IGF1 signaling pathways. They found that DR-resistant cell lines had mutations that led to constitutive PI3K signaling, whereas DR-sensitive cell lines did not. Indeed, replacement of an allele encoding a constitutively active mutant of PI3K with one encoding wild-type PI3K was sufficient to convert cells from a DR-resistant phenotype to a DR-sensitive one. DR-sensitive tumors exhibited increased apoptosis rather than decreased proliferation when exposed to DR, and this correlated with the increased activity of the transcription factor FOXO1, a downstream target of Akt that activates genes encoding proapoptotic factors. Together, these data suggest that the extent of PI3K signaling in tumor cells determines their sensitivity to the effects of DR-type therapies.
N. Y. Kalaany, D. M. Sabatini, Tumours with PI3K activation are resistant to dietary restriction. Nature 458, 725–731 (2009). [PubMed]
A. Brunet, When restriction is good. Nature 458, 713–714 (2009). [PubMed]