FoxO1 is involved in the antineoplastic effect of calorie restriction.
The FoxO transcription factors may be involved in the antiaging effect of calorie restriction (CR) in mammals. To test the hypothesis, we used FoxO1 knockout heterozygotic (HT) mice, in which the FoxO1 mRNA level was reduced by 50%, or less, of that in wild-type (WT) mouse tissues. The WT and HT mice were fed ad libitum (AL) or 30% CR diets from 12 weeks of age. Aging- and CR-related changes in body weight, food intake, blood glucose, and insulin concentrations were similar between the WT and HT mice in the lifespan study. The response to oxidative stress, induced by intraperitoneal injection of 3-nitropropionic acid (3-NPA), was evaluated in the liver and hippocampus at 6 months of age. Several of the selected FoxO1-target genes for cell cycle arrest, DNA repair, apoptosis, and stress resistance were up-regulated in the WT-CR tissues after 3-NPA injection, while the effect was mostly diminished in the HT-CR tissues. Of these gene products, we focused on the nuclear p21 protein level in the liver and confirmed its up-regulation only in the WT-CR mice in response to oxidative stress. The lifespan did not differ significantly between the WT and HT mice in AL or CR conditions. However, the antineoplastic effect of CR, as indicated by reduced incidence of tumors at death in the WT-CR mice, was mostly abrogated in the HT-CR mice. The present results suggest a role for FoxO1 in the antineoplastic effect of CR through the induction of genes responsible for protection against oxidative and genotoxic stress.
Yamaza
Haruyoshi
H
Department of Investigative Pathology, Nagasaki University, Japan.
Komatsu
Toshimitsu
T
Wakita
Saori
S
Kijogi
Carole
C
Park
Seongjoon
S
Hayashi
Hiroko
H
Chiba
Takuya
T
Mori
Ryoichi
R
Furuyama
Tatsuo
T
Mori
Nozomu
N
Shimokawa
Isao
I
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D031204:Caloric Restriction; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D005786:Gene Expression Regulation; D007328:Insulin / Q000097:blood; D008136:Longevity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics
D001786:Blood Glucose; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D012333:RNA, Messenger