DIETARY RESTRICTION REDUCES INSULIN-LIKE-GROWTH-FACTOR-I LEVELS, WHICH MODULATES APOPTOSIS, CELL-PROLIFERATION, AND TUMOR PROGRESSION IN P53-DEFICIENT MICE

Diet contributes to over one-third of cancer deaths in the Western wor ld, yet the factors in the diet that influence cancer are not elucidat ed, A reduction in caloric intake dramatically slows cancer progressio n in rodents, and this may be a major contribution to dietary effects on cancer, Insulin-like growth factor I (IGF-I) is lowered during diet ary restriction (DR) in both humans and rats, Because IGF-I modulates cell proliferation, apoptosis, and tumorigenesis, the mechanisms behin d the protective effects of DR may depend on the reduction of this mul tifaceted growth factor, To test this hypothesis, IGF-I was restored d uring DR to ascertain if lowering of IGF-I was central to slowing blad der cancer progression during DR. Heterozygous p53-deficient mice rece ived a bladder carcinogen, p-cresidine, to induce preneoplasia, After confirmation of bladder urothelial preneoplasia, the mice were divided into three groups: (a) ad libitum; (b) 20% DR; and (c) 20% DR plus IG F-I (IGF-I/DR). Serum IGF-I was lowered 24% by DR but was completely r estored in the IGF-I/DR-treated mice using recombinant IGF-I administe red via osmotic minipumps, Although tumor progression was decreased by DR, restoration of IGF-I serum levels in DR-treated mice increased th e stage of the cancers, Furthermore, IGF-I modulated tumor progression independent of changes in body weight, Rates of apoptosis in the pren eoplastic lesions were 10 times higher in DR-treated mice compared to those in IGF/DR- and ad libitum-treated mice, Administration of IGF-I to DR-treated mice also stimulated cell proliferation 6-fold in hyperp lastic foci, In conclusion, DR lowered IGF-I levels, thereby favoring apoptosis over cell proliferation and ultimately slowing tumor progres sion, This is the first mechanistic study demonstrating that IGF-I sup plementation abrogates the protective effect of DR on neoplastic progr ession.