Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton streets, BLSC L3-314, Buffalo, NY 14263, USA.
Cancer Prev Res (Phila). 2011 Nov;4(11):1825-34. doi: 10.1158/1940-6207.CAPR-11-0140. Epub 2011 Aug 11.
Dietary folate is essential in all tissues to maintain several metabolite pools and cellular proliferation. Prostate cells, due to specific metabolic characteristics, have increased folate demand to support proliferation and prevent genetic and epigenetic damage. Although several studies have found that dietary folate interventions can affect colon cancer biology in rodent models, its impact on prostate is unknown. The purpose of this study was to determine whether dietary folate manipulation, possibly being of primary importance for prostate epithelial cell metabolism, could significantly affect prostate cancer progression. Strikingly, mild dietary folate depletion arrested prostate cancer progression in 25 of 26 transgenic adenoma of the mouse prostate (TRAMP) mice, in which tumorigenesis is prostate-specific and characteristically aggressive. The significant effect on prostate cancer growth was characterized by size, grade, proliferation, and apoptosis analyses. Folate supplementation had a mild, nonsignificant, beneficial effect on grade. In addition, characterization of folate pools (correlated with serum), metabolite pools (polyamines and nucleotides), genetic and epigenetic damage, and expression of key biosynthetic enzymes in prostate tissue revealed interesting correlations with tumor progression. These findings indicate that prostate cancer is highly sensitive to folate manipulation and suggest that antifolates, paired with current therapeutic strategies, might significantly improve treatment of prostate cancer, the most commonly diagnosed cancer in American men.
饮食中的叶酸对于维持各种代谢物池和细胞增殖在所有组织中都是必不可少的。由于特定的代谢特征，前列腺细胞对叶酸的需求增加，以支持增殖并防止遗传和表观遗传损伤。尽管几项研究发现，饮食中叶酸的干预可以影响啮齿动物模型中的结肠癌生物学，但它对前列腺的影响尚不清楚。本研究的目的是确定饮食中叶酸的操纵是否可能对前列腺上皮细胞的代谢至关重要，是否会显著影响前列腺癌的进展。令人惊讶的是，轻度饮食叶酸缺乏症在 26 只转基因前列腺癌小鼠（TRAMP）中的 25 只中阻止了前列腺癌的进展，其中肿瘤发生是前列腺特异性的，且具有侵袭性。叶酸补充对肿瘤分级有轻微但无统计学意义的有益作用。此外，对叶酸池（与血清相关）、代谢物池（多胺和核苷酸）、遗传和表观遗传损伤以及前列腺组织中关键生物合成酶的表达进行的特征描述与肿瘤进展有有趣的相关性。这些发现表明，前列腺癌对叶酸的操纵非常敏感，并表明抗叶酸药物与当前的治疗策略相结合，可能会显著改善前列腺癌的治疗效果，前列腺癌是美国男性最常见的癌症。
