Modulation of prostate cancer genetic risk by omega-3 and omega-6 fatty acids
Isabelle M. Berquin, … , Jing X. Kang, Yong Q. Chen
Isabelle M. Berquin, … , Jing X. Kang, Yong Q. Chen
Published July 2, 2007
Citation Information: J Clin Invest. 2007;117(7):1866-1875. https://doi.org/10.1172/JCI31494.
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Research Article Oncology

Modulation of prostate cancer genetic risk by omega-3 and omega-6 fatty acids

Abstract

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.

Authors

Isabelle M. Berquin, Younong Min, Ruping Wu, Jiansheng Wu, Donna Perry, J. Mark Cline, Mike J. Thomas, Todd Thornburg, George Kulik, Adrienne Smith, Iris J. Edwards, Ralph D’Agostino Jr., Hao Zhang, Hong Wu, Jing X. Kang, Yong Q. Chen

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Figure 7

Dependence on Bad for omega-3 PUFA–induced cell death.

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Dependence on Bad for omega-3 PUFA–induced cell death. (A) PC3 cells wer...
(A) PC3 cells were infected with lentivirus expressing scrambled shRNA (C shRNA) or Bad-specific shRNA (Bad shRNA) or mock infected (no shRNA) for 2 days. Cells were seeded and incubated with FAs for 6 days, then photographed using a fluorescence microscope. The presence of lentivirus is evidenced by GFP expression. Western blotting was performed to confirm the successful knockdown of Bad in both PC3 and LNCaP cells. Day 0, prior to FA treatment; day 6, after incubation with media containing FA for 6 days. C, control. (B) Live and dead cells were enumerated by the trypan blue exclusion method using a hemocytometer. P values were determined by Student’s t test. LNCaP cells have higher background apoptosis compared with PC3 cells, but omega-3 FA treatment increased apoptosis approximately 4-fold in both cell lines.(C) LNCaP cells were transfected with control vector or mouse Bad expression vector. G418-resistant colonies were isolated, verified for successful expression of the HA-tagged mouse Bad by Western blotting, and pooled. Vector control– (V) and mouse Bad–expressing (mBad) LNCaP cells were infected with shRNA lentivirus as described above. Cells were incubated with FAs for 6 days, and live and dead cells were enumerated as described above. Cell lysates were used for confirmation of successful knockdown of the endogenous Bad but not the exogenous mouse Bad (whose sequence varies from human Bad in the region targeted by the shRNA).