Modulation of prostate cancer genetic risk by omega-3 and omega-6 fatty acids.
Although a causal role of genetic alterations in human cancer is well established, it is still unclear whether dietary fat can modulate cancer risk in a predisposed population. Epidemiological studies suggest that diets rich in omega-3 polyunsaturated fatty acids reduce cancer incidence. To determine the influence of fatty acids on prostate cancer risk in animals with a defined genetic lesion, we used prostate-specific Pten-knockout mice, an immune-competent, orthotopic prostate cancer model, and diets with defined polyunsaturated fatty acid levels. We found that omega-3 fatty acids reduced prostate tumor growth, slowed histopathological progression, and increased survival, whereas omega-6 fatty acids had opposite effects. Introducing an omega-3 desaturase, which converts omega-6 to omega-3 fatty acids, into the Pten-knockout mice reduced tumor growth similarly to the omega-3 diet. Tumors from mice on the omega-3 diet had lower proportions of phosphorylated Bad and higher apoptotic indexes compared with those from mice on omega-6 diet. Knockdown of Bad eliminated omega-3-induced cell death, and introduction of exogenous Bad restored the sensitivity to omega-3 fatty acids. Our data suggest that modulation of prostate cancer development by polyunsaturated fatty acids is mediated in part through Bad-dependent apoptosis. This study highlights the importance of gene-diet interactions in prostate cancer.
Berquin
Isabelle M
IM
Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Min
Younong
Y
Wu
Ruping
R
Wu
Jiansheng
J
Perry
Donna
D
Cline
J Mark
JM
Thomas
Mike J
MJ
Thornburg
Todd
T
Kulik
George
G
Smith
Adrienne
A
Edwards
Iris J
IJ
D'Agostino
Ralph
R
Zhang
Hao
H
Wu
Hong
H
Kang
Jing X
JX
Chen
Yong Q
YQ
D000818:Animals; D017209:Apoptosis; D018450:Disease Progression; D015525:Fatty Acids, Omega-3 / Q000378:metabolism / Q000494:pharmacology*; D043371:Fatty Acids, Omega-6 / Q000378:metabolism / Q000494:pharmacology*; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000178:diet therapy / Q000235:genetics* / Q000473:pathology*; D015996:Survival Rate; D051025:bcl-Associated Death Protein / Q000378:metabolism
C494820:Bad protein, mouse; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D051025:bcl-Associated Death Protein; D051059:PTEN Phosphohydrolase