Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Sedanstrasse 115, Osnabrück, D-49090, Germany.
Nutr Metab (Lond). 2012 Aug 14;9(1):74. doi: 10.1186/1743-7075-9-74.
Prostate cancer (PCa) is dependent on androgen receptor signaling and aberrations of the PI3K-Akt-mTORC1 pathway mediating excessive and sustained growth signaling. The nutrient-sensitive kinase mTORC1 is upregulated in nearly 100% of advanced human PCas. Oncogenic mTORC1 signaling activates key subsets of mRNAs that cooperate in distinct steps of PCa initiation and progression. Epidemiological evidence points to increased dairy protein consumption as a major dietary risk factor for the development of PCa. mTORC1 is a master regulator of protein synthesis, lipid synthesis and autophagy pathways that couple nutrient sensing to cell growth and cancer. This review provides evidence that PCa initiation and progression are promoted by cow´s milk, but not human milk, stimulation of mTORC1 signaling. Mammalian milk is presented as an endocrine signaling system, which activates mTORC1, promotes cell growth and proliferation and suppresses autophagy. Naturally, milk-mediated mTORC1 signaling is restricted only to the postnatal growth phase of mammals. However, persistent consumption of cow´s milk proteins in humans provide highly insulinotropic branched-chain amino acids (BCAAs) provided by milk´s fast hydrolysable whey proteins, which elevate postprandial plasma insulin levels, and increase hepatic IGF-1 plasma concentrations by casein-derived amino acids. BCAAs, insulin and IGF-1 are pivotal activating signals of mTORC1. Increased cow´s milk protein-mediated mTORC1 signaling along with constant exposure to commercial cow´s milk estrogens derived from pregnant cows may explain the observed association between high dairy consumption and increased risk of PCa in Westernized societies. As well-balanced mTORC1-signaling plays an important role in appropriate prostate morphogenesis and differentiation, exaggerated mTORC1-signaling by high cow´s milk consumption predominantly during critical growth phases of prostate development and differentiation may exert long-term adverse effects on prostate health. Attenuation of mTORC1 signaling by contemporary Paleolithic diets and restriction of dairy protein intake, especially during mTORC1-dependent phases of prostate development and differentiation, may offer protection from the most common dairy-promoted cancer in men of Western societies.
前列腺癌（PCa）依赖于雄激素受体信号和 PI3K-Akt-mTORC1 途径的异常，该途径介导过度和持续的生长信号。营养敏感激酶 mTORC1 在近 100%的晚期人类 PCa 中上调。致癌的 mTORC1 信号激活关键的 mRNA 子集，这些子集在 PCa 起始和进展的不同步骤中协同作用。流行病学证据表明，增加牛奶蛋白的摄入是导致 PCa 发展的主要饮食风险因素。mTORC1 是蛋白质合成、脂质合成和自噬途径的主要调节因子，这些途径将营养感应与细胞生长和癌症联系起来。本综述提供的证据表明，PCa 的起始和进展是由牛奶而不是人乳刺激 mTORC1 信号所促进的。哺乳动物奶被认为是一种内分泌信号系统，它激活 mTORC1，促进细胞生长和增殖，并抑制自噬。自然地，牛奶介导的 mTORC1 信号仅在哺乳动物的出生后生长阶段受到限制。然而，人类持续摄入牛奶蛋白会提供牛奶快速水解的乳清蛋白所提供的高胰岛素刺激支链氨基酸（BCAAs），这些氨基酸会升高餐后血浆胰岛素水平，并通过酪蛋白衍生的氨基酸增加肝 IGF-1 血浆浓度。BCAAs、胰岛素和 IGF-1 是 mTORC1 的关键激活信号。增加的牛奶蛋白介导的 mTORC1 信号以及持续暴露于来自怀孕奶牛的商业牛奶雌激素可能解释了高乳制品消费与西方社会中 PCa 风险增加之间的观察到的关联。由于平衡的 mTORC1 信号在适当的前列腺形态发生和分化中起着重要作用，因此在前列腺发育和分化的关键生长阶段大量摄入牛奶会导致 mTORC1 信号过度，这可能对前列腺健康产生长期的不利影响。通过当代旧石器时代饮食来减弱 mTORC1 信号和限制乳制品蛋白的摄入，特别是在前列腺发育和分化依赖于 mTORC1 的阶段，可能会为西方社会男性提供免受最常见的牛奶促进的癌症的保护。
