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Epidemiological evidence points to increased dairy protein consumption as a major dietary risk factor for the development of PCa. Mammalian milk is presented as an endocrine signaling system, which activates mTORC1, promotes cell growth and proliferation and suppresses autophagy. 10 mb sclerosis Prostata- milk-mediated mTORC1 signaling is restricted only to the postnatal growth phase of mammals.
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.
Prostate cancer PCa is the most commonly diagnosed malignancy in males living in highly developed and industrialized countries of Europe and North America. In these Western countries high PCa incidence rates 10 mb sclerosis Prostata- 80 and perper year are observed, while incidence rates of PCa in western, southeastern and eastern Asia and eastern and northern Africa range between 10 and 20 perper year [ 1 ].
There were an estimatednew PCa diagnoses and 32, deaths in 10 mb sclerosis Prostata- United States duringwhich makes PCa the second leading cause of cancer death in men. Several lines of evidence confirmed that Western diet is related to PCa risk and outcome [ 2 - 5 ].
In addition, per capita consumption of milk and dairy products correlates positively with both 10 mb sclerosis Prostata- incidence and mortality [ 67 ].
Diets of wealthy well-developed countries are characterized by high dairy protein and meat consumption. In Japan the mortality of PCa increased fold linearly after World War 2 associated with an increase in the intake of milk foldmeat 9-fold and eggs 7-foldrespectively [ 10 mb sclerosis Prostata- ].
The Health Professionals Study demonstrated a strong association between calcium intake and prostate cancer risk [ 9 ]. Dairy proteins are a significant dietary source of calcium. Whereas, Giovannucci et al. The European Prospective Investigation into Cancer and Nutrition examined animal food, protein and calcium consumption and the risk of PCa inmen during an 8.
Annual increase of per capita cheese consumption in Germany. Cheese is a rich source of the mTORC1-activating amino 10 mb sclerosis Prostata- leucine. Cheese consumption steadily increased in industrialized countries like Germany. Remarkably, calcium from dairy products was positively associated with PCa risk, but not calcium from other foods [ 10 ]. 10 mb sclerosis Prostata- observation questions the role of dairy-derived calcium and points to a more critical role of the milk protein fraction itself.
In fact, Ahn et al. Moreover, the calcium-vitamin-D hypothesis has been challenged at the level of cell biology by Heaney [ 12 ]. In this paper, evidence will be provided that the intrinsic signaling capability of the dairy protein itself is the most critical nutritional factor linking milk and dairy products to the pathogenesis of PCa. Several ecological, cohort and case control studies conducted in various countries [ 10 mb sclerosis Prostata-8 - 1113 - 21 ] have provided evidence for the association 10 mb sclerosis Prostata- increased 10 mb sclerosis Prostata- and dairy intake and increased risk of PCa, which has been confirmed by meta-analyses and systematic 10 mb sclerosis Prostata- [ 22 - 25 ].
However, two studies, the prospective cohort study of Rodriguez et al. In contrast, Raimondi et al. Ganmaa et al. Notably, populations with low dairy protein intake like the Inuit and Alaska native men exhibit an extremely low incidence and mortality rate of PCa [ 2829 ].
It is alarming, that daily milk consumption in adolescence has recently been associated with a 3. Notably, milk and dairy consumption has been linked to an increased incidence of acne in adolescence [ 31 - 35 ]. Severe acne in adolescence has been related to an increased risk of PCa in adulthood [ 36 ]. The association between PCa and acne might already point to overstimulated mTORC1-signaling of the androgen-dependent sebaceous gland and prostate gland during puberty as the underlying common cause of aberrant signal transduction [ 37 ].
As the majority of controlled studies have shown a dose-related association between dairy protein intake and increased risk of PCa, the underlying mechanism of dairy-induced PCa has not yet been identified. The calcium hypothesis [ 938 ], however, does not explain the cancer promoting effects of dairy protein intake as non-dairy-derived calcium showed no relation to an increased 10 mb sclerosis Prostata- of PCa [ 10 ].
Neither intake of calcium from dairy products nor calcium supplements were associated with PCa risk in a prospective study of Koh et al. Neither high calcium nor high phosphate intake of dairy products have been shown to change intracellular concentrations of 1,25 OH 2 D in PCa cells. Intracellular 1,25 OH 2 D concentrations are primarily regulated by intracellular synthesis and not by 1,25 OH 10 mb sclerosis Prostata- D uptake from the circulation [ 12 ].
Thus, neither the calcium hypothesis [ 38 ] nor the phosphorus hypothesis of PCa [ 40 ] provide reasonable tumorigenic mechanisms compatible with recent insights into the molecular biology of vitamin D, which could explain the proliferative cellular effects of dairy intake, thus calling both hypotheses of PCa into question. It is the major purpose of this paper to provide evidence that dairy protein-derived amino acids provide the cancer-promoting effect of dairy by introducing mammalian milk as a fundamental growth-promoting mTORC1-signaling system of mammalian evolution.
This observation implies that the hormonal compounds of commercial cows milk like estrogens and IGF-1 are not the 10 mb sclerosis Prostata- stimuli of milk-induced PCa cell growth, but rather points to the role of amino acids derived from hydrolysed milk proteins.
This in vitro evidence fits well with recent epidemiological data from a cohort of 3, men diagnosed with apparently localized PCa. In this cohort, high versus low intakes of whole milk substantially increased the risk of PCa progression [ 42 ]. To understand the biological impact of milk in prostate tumorigenesis, the signal transduction pathways driven by mammalian milk, an mTORC1-signaling system naturally confined to the neonatal growth period, must be examined in greater detail.
Milk signaling is integrated and mediated by the nutrient-sensitive kinase 10 mb sclerosis Prostata- mammalian target of rapamycin complex 1. The 10 mb sclerosis Prostata- signaling pathway has become a major focus of human cancer research [ 43 ]. 10 mb sclerosis Prostata- is thus of utmost importance to understand the nutrient-mediated signaling pathways regulating mTORC1, the central hub 10 mb sclerosis Prostata- cell signaling, cell growth and cell proliferation.
In contrast to mTORC2, which contains the partner protein Rictoronly mTORC1 plays a special role in sensing cellular nutrients, amino acids, and energy ATP levels, which are important stimuli for cell 10 mb sclerosis Prostata- and proliferation. Most functions of mTORC1 are inhibited by rapamycin, a triene 10 mb sclerosis Prostata- antibiotic synthesized by Streptomyces hygroscopicus [ 51 ].
The activity of Rheb is tightly regulated by the tuberous sclerosis proteins TSC1 hamartin and TSC2 tuberinwhich form a functional heterodimeric complex. Synopsis of major pathways activating mTORC1. The activating signals of the growth factors insulin and IGF-1 and the energy source glucose are mediated by attenuating the inhibitory function of TSC2 towards Rheb. See list of abbreviations.
In Western diet hyperglycemic food compounds are frequently combined with dairy products like cornflakes with milk or pizza and burgers combined with cheese.
Notably, leucine 10 mb sclerosis Prostata- been identified as the primarily responsible branched-chain amino acid for mTORC1-dependent stimulation of skeletal muscle protein synthesis [ 52 ].
In fact, in response to amino acid depletion, mTORC1 activity is rapidly abolished [ 62 ]. From all essential amino acids, leucine exerts the greatest effects on mTORC1 signaling [ 42485162 ]. Recent evidence has been provided that amino acids and especially leucine promote the cellular translocation of inactive mTORC1 to lysosomal compartments enriched in activated Rheb [ 5355 ]. This spatial regulation of inactive mTORC1 by amino acids is mediated by an active Rag heterodimerwhich is of utmost biological importance for amino acid sensing by mTORC1.
Insulin is not able to activate the mTORC1 pathway when cells are deprived of amino acids [ 64 ]. Indeed, both insulin- and amino acid signaling are required for maximal mTORC1 activity [ 65 ]. Growing cells and especially proliferating tumor cells not only require increased amounts of amino acids and protein but also high amounts of lipids to enlarge their cellular membrane compartments. It is thus not surprising that the key transcription factor of lipid biosynthesis SREBP-1 sterol regulatory element binding protein-1 is dependent on upstream activation of mTORC1 [ 6667 ].
Increased insulin, IGF-1 and especially leucine signaling with activation of mTORC1 are not only a requirement for physiological growth during the neonatal period and puberty but play a pivotal role in the process of tumorigenesis [ 4368 - 74 ]. In addition to various other cancers, signaling pathways that activate mTORC1 are frequently deregulated in PCa [ 437475 ]. PTEN, phosphatase and tensin homologue deleted on chromosome 10, is a negative regulator of Akt activation, as it converts phosphatidylinositol 3,4,5-triphosphate [PtdIns 3,4,5 P 3 back to PtdIns 4,5 P 2leading to reduced recruitment of Akt to the cell membrane, which is the important location for PDKmediated final phosphorylation and full activation of Akt [ 80 ].
Compelling evidence has recently demonstrated that mTORC1 controls the translational program 10 mb sclerosis Prostata- mRNA subsets of genes involved in PCa initiation, invasion and metastasis [ 89 - 91 ]. Genetic loss of either mTOR 10 mb sclerosis Prostata- Akt1 is sufficient to signifcantly reduce initiation of PCa in the conditional Pten mouse model [ 90 - 92 ]. The allosteric mTORC1 inhibitor rapamycin has been shown to revert Akt-dependent early prostate intraepithelial neoplasia PIN in young mice through regulation of apoptotic and HIFdependent pathways [ 93 ].
It has been shown in the prostate-specific 10 mb sclerosis Prostata- -deleted mouse model of PCa that depletion of androgens significantly inhibited tumor growth progression without altering the activation of Akt and mTOR, however, the combination of antiandrogen treatment with rapamycin-mediated mTORC1 inhibition exhibited additive antitumor effects [ 94 ]. Androgens rapidly reduced the protein concentration of the cell cycle inhibitor 10 mb sclerosis Prostata- in PCa cells by increasing proteasome-mediated degradation of p27 [ 99 ].
Androgens increased 10 mb sclerosis Prostata- Akt S phosphorylation, which stimulated Akt-mediated phosphorylation of p27 Tthe critical signal for p27 proteasomal degradation [ 99 ]. Furthermore, androgen-mTORC2-mediated activation of Akt resulted 10 mb sclerosis Prostata- increased phosphorylation of FoxO1, which in its phosphorylated form is extruded from the nucleus into the cytoplasm [ 99 10 mb sclerosis Prostata.
Recently, Hsieh et al. Thus, substantial evidence underlines the pivotal role of exaggerated mTORC1 signaling in both PCa development and progression. Continuously increased mTORC1 signaling has been associated with tumor initiation as well as tumor progression [ 91 ]. In fact, sustained proliferative signaling has been identified as a hallmark of cancer and comprises the most important biological capability during the multistep development of human tumors [ ].
To understand the impact of dairy protein consumption on PCa tumorigenesis, we have to appreciate the signal transduction of mammalian milk. The function of mammalian milk is not only to provide sufficient calories and nutrients to the newborn but in parallel to promote postnatal growth by milk-mediated growth factor 10 mb sclerosis Prostata. For adequate species-specific growth requirements, each mammalian species has developed its own species-specific magnitude of milk-mediated mTORC1 signaling.
The strength of mTORC1-mediated stimulation of mammalian growth is 10 mb sclerosis Prostata- with the total protein and total leucine concentration in mammalian milk [ ]. The milk of various mammalian species shows significant species-dependent variations in the concentration of total milk protein.
However, milk of all mammals exhibit 10 mb sclerosis Prostata- constant ratio of 0,1 g of leucine per 1 g of total milk protein [ ]. Remarkably, species with the highest milk protein concentration exhibit the most rapid growth rate. The rat doubles birth weight already after 4 days, the cat after 10 days, the calf after 40 days, and the human neonate, the mammal with the slowest growth rate, after days, respectively [ ].
The great differences in the magnitude of mTORC1 signaling may explain the differences in growth velocity and weight gain between Bos taurus and Homo sapiens.
Moreover, the relatively low mTORC1 signaling axis of human neonates in comparison to Bos 10 mb sclerosis Prostata- allows a slower rate of brain growth permitting more time for the accumulation of long-chain omega-6 polyunsaturated fatty acids specifically n6 and long-chain omega-3 polyunsaturated fatty acids specifically n3critical nutrients for the development of complex brain functions, an evolutionary advantage of Homo sapiens [ ].
With regard to mTORC1-dependent postnatal events in prostate morphogenesis and prostate gland development it is of special concern 10 mb sclerosis Prostata- infant formula feeding in comparison to natural breast-feeding may over-stimulate mTORC1 signaling thereby disturbing physiological conditions of prostate growth and development during the postnatal period. Milk signaling, prostate gland morphogenesis and tumorigenesis.
A Signaling of human milk and physiological prostate morphogenesis. It has been demonstrated in rat hepatocyte primary cultures that hepatic IGF-1 gene expression directly depends upon the availability of essential amino acids [ ]. Elevated IGF-1 serum concentrations are associated with consumption of animal versus vegetable proteins.
Furthermore, skim milk protein versus meat intake increased serum IGF-1 10 mb sclerosis Prostata- in 8-year-old boys [ ], underlining the higher IGFenhancing activity of milk proteins in comparison to meat protein. In prepubertal boys, casein versus whey protein elicited a greater rise in plasma IGF-1 concentrations, whereas whey protein versus casein elicited a greater rise in postprandial insulin plasma concentrations [ ].
Therefore, it is reasonable to differentiate between signaling proteins like milk proteins and structural proteins like meat and fish protein, which are less efficient in elevating insulin and IGF-1 plasma concentrations than milk proteins. Lower IGF-1 signaling due to mutations with reduced activity of the IGF-1 receptor are associated with longevity and lower incidence rates of cancer [ ].
Moreover, congenital IGF-1 deficiency has been shown to confer protection against the development of malignancies in humans including a lower prevalence of PCa [ ]. In accordance with observed cancer-protective effects of low IGF-1 10 mb sclerosis Prostata- is a recent epidemiological study, which demonstrated that high serum IGF-1 concentrations were associated with increased cancer deaths in older men [ ]. Notably, men with type 2 diabetes were found to have a lower incidence of PCa, presumably due to decreased IGF-1 serum levels [ ].
However, recent large cohort studies have reported the association of type 2 diabetes with advanced high-grade PCa [ ].