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.
Introduction
A causal role of genetic alterations in human cancer is well established; however, environmental influence on cancer risk is not clearly understood. Over 2 decades, epidemiologic studies have been reported on the effect of dietary fat on prostate cancer risk. However, the mechanistic role of dietary fat in prostate cancer remains ill defined. Prostate cancer is the most frequently diagnosed cancer and a leading cause of cancer death in men in the US. There is a wide variation in international prostate cancer mortality rates; these are particularly high in Northern Europe and North America and much lower in Japan and other Asian countries. Yet small, latent carcinomas of the prostate diagnosed at autopsy are as common in Asian countries as in Western countrie. Immigrants from Poland and Japan exhibit a significant increase in the risk of developing clinical prostate cancer when resident in the US. These findings implicate environmental variables, and possibly diet, as significant contributing factors.
Omega-3 and omega-6 polyunsaturated FAs (PUFAs) are essential FAs: mammals can neither synthesize them de novo nor interconvert them; therefore, they have to be taken in from diet. Many vegetable oils contain high levels of omega-6 PUFAs, whereas fish oil is a rich source of omega-3 PUFAs, mainly eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3). Diets with an omega-6/omega-3 PUFA ratio of 1 are recommended for human consumption by a panel of nutritionists, and diets with a similar ratio are consumed by some populations such as the Inuit . Current Western diets have omega-6/omega-3 ratios of approximately 30 , although they can be as high as 50. Some evidence suggests that cyclooxygenase inhibitors, which block the metabolism of omega-6 PUFAs, are beneficial in prevention of colon and prostate cancer. However, the cardiovascular toxicity of cyclooxygenase-2 inhibitors has jeopardized the clinical utility of these drugs. Reducing the intake of omega-6 PUFAs and increasing the proportion of dietary omega-3 is an attractive approach.
Inaccuracy in reporting dietary intake and difficulties in conducting mechanistic studies on human populations have hampered investigations on the role of dietary fat in prostate cancer development. Most experiments using animals have been performed in xenograft models and are limited by the fact that tumors grow at an ectopic site in an immune-deficient host environment. Moreover, dietary composition in animal diets is often poorly defined, and dietary intake is inadequately monitored. In an effort to overcome these limitations, we used prostate-specific Pten-knockout mice, an immune-competent, orthotopic prostate cancer model, and designed diets to investigate the influence of dietary PUFAs on prostate cancer risk in animals with this defined genetic lesion.
Resource: http://www.ncbi.nlm.nih.gov/
Resource: http://www.nutritionforest.com/
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.
Introduction
A causal role of genetic alterations in human cancer is well established; however, environmental influence on cancer risk is not clearly understood. Over 2 decades, epidemiologic studies have been reported on the effect of dietary fat on prostate cancer risk. However, the mechanistic role of dietary fat in prostate cancer remains ill defined. Prostate cancer is the most frequently diagnosed cancer and a leading cause of cancer death in men in the US. There is a wide variation in international prostate cancer mortality rates; these are particularly high in Northern Europe and North America and much lower in Japan and other Asian countries. Yet small, latent carcinomas of the prostate diagnosed at autopsy are as common in Asian countries as in Western countrie. Immigrants from Poland and Japan exhibit a significant increase in the risk of developing clinical prostate cancer when resident in the US. These findings implicate environmental variables, and possibly diet, as significant contributing factors.
Omega-3 and omega-6 polyunsaturated FAs (PUFAs) are essential FAs: mammals can neither synthesize them de novo nor interconvert them; therefore, they have to be taken in from diet. Many vegetable oils contain high levels of omega-6 PUFAs, whereas fish oil is a rich source of omega-3 PUFAs, mainly eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3). Diets with an omega-6/omega-3 PUFA ratio of 1 are recommended for human consumption by a panel of nutritionists, and diets with a similar ratio are consumed by some populations such as the Inuit . Current Western diets have omega-6/omega-3 ratios of approximately 30 , although they can be as high as 50. Some evidence suggests that cyclooxygenase inhibitors, which block the metabolism of omega-6 PUFAs, are beneficial in prevention of colon and prostate cancer. However, the cardiovascular toxicity of cyclooxygenase-2 inhibitors has jeopardized the clinical utility of these drugs. Reducing the intake of omega-6 PUFAs and increasing the proportion of dietary omega-3 is an attractive approach.
Inaccuracy in reporting dietary intake and difficulties in conducting mechanistic studies on human populations have hampered investigations on the role of dietary fat in prostate cancer development. Most experiments using animals have been performed in xenograft models and are limited by the fact that tumors grow at an ectopic site in an immune-deficient host environment. Moreover, dietary composition in animal diets is often poorly defined, and dietary intake is inadequately monitored. In an effort to overcome these limitations, we used prostate-specific Pten-knockout mice, an immune-competent, orthotopic prostate cancer model, and designed diets to investigate the influence of dietary PUFAs on prostate cancer risk in animals with this defined genetic lesion.
Resource: http://www.ncbi.nlm.nih.gov/
Resource: http://www.nutritionforest.com/
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