Dietary folate deficiency blocks prostate cancer progression in the TRAMP model.
Dietary folate deficiency blocks prostate cancer progression in the TRAMP model.
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DOI：
10.1158/1940-6207.capr-11-0140
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Smiraglia DJ
中科院分区：
文献类型：
--
作者：
Bistulfi G;Foster BA;Karasik E;Gillard B;Miecznikowski J;Dhiman VK;Smiraglia DJ
膳食叶酸对于所有组织维持多种代谢物库和细胞增殖至关重要。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。尽管一些研究发现膳食叶酸干预可以影响啮齿动物模型中的结肠癌生物学，但对前列腺的影响尚不清楚。本研究的目的是确定膳食叶酸的控制（可能对前列腺上皮细胞代谢至关重要）是否可以显着影响前列腺癌（CaP）的进展。引人注目的是，轻度膳食叶酸消耗可阻止 25/26 转基因 TRAMP 小鼠的 CaP 进展，其中肿瘤的发生是前列腺特异性的且具有典型的侵袭性。通过大小、等级、增殖和凋亡分析来表征对 CaP 生长的显着影响。补充叶酸对成绩有轻微但不显着的有益影响。此外，叶酸库（与血清相关）、代谢物库（多胺、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的特征揭示了与肿瘤进展的有趣相关性。这些研究结果表明，CaP 对叶酸操作高度敏感，并表明抗叶酸药物与当前的治疗策略相结合，可能会显着改善 CaP（美国男性中最常诊断出的癌症）的治疗。
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 found that dietary folate interventions can affect colon cancer biology in rodent models, impact on prostate is unknown. The purpose of this study was to determine if dietary folate manipulation, possibly being of primary importance for prostate epithelial cell metabolism, could significantly affect prostate cancer (CaP) progression. Strikingly, mild dietary folate depletion arrested CaP progression in 25/26 transgenic TRAMP mice, where tumorigenesis is prostate specific and characteristically aggressive. The significant effect on CaP growth was characterized by size, grade, proliferation and apoptosis analyses. Folate supplementation had a mild, non significant beneficial effect on grade. In addition, characterization of folate pools (correlated with serum), metabolite pools (polyamines, nucleotides), genetic and epigenetic damage, and expression of key biosynthetic enzymes in prostate tissue revealed interesting correlations with tumor progression. These findings indicate that CaP is highly sensitive to folate manipulation and suggest that antifolates, paired to current therapeutic strategies, might significantly improve treatment of CaP, the most commonly diagnosed cancer in American men.