Abstract
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.
Highlights
Prostate cancer (PCa) is the most commonly diagnosed malignancy in males living in highly developed and industrialized countries of Europe and North America
Inhibition of either LAT3 or LAT1 can lead to decreased growth of PCa cells [97]. It is conceivable, that the total dietary leucine influx as wells as androgen- and estrogen-regulated intracellular leucineuptake mechanisms play important roles for the regulation of leucine-mediated Mammalian target of rapamycin complex 1 (mTORC1) signaling. These findings suggest that preliminary therapeutic responses to Androgen deprivation therapy (ADT) may be related to attenuation of androgendependent leucine-mediated activation of mTORC1 [97], a therapeutic mechanism, which may be counterbalanced by high intake of commercial cows milk protein
Milks functionality depends on its stimulation of the nutrient-sensitive kinase mTORC1, the critical hub regulating cell growth, proliferation, autophagy and metabolic programming
Summary
Prostate cancer (PCa) is the most commonly diagnosed malignancy in males living in highly developed and industrialized countries of Europe and North America. Cows milk protein elevates IGF-1 serum levels: a known risk factor of prostate cancer Insulin-like growth factor-1 (IGF-1) is an important activator of PI3K/Akt signaling resulting in mTORC1 activation [57,60,68] It has been demonstrated in rat hepatocyte primary cultures that hepatic IGF-1 gene expression directly depends upon the availability of essential amino acids [115]. Substantial evidence supports the view that milk signaling shares synergistic effects with oncogenic mTORC1 signaling pathways of PCa. Commercial milk intake by increasing plasma concentrations of insulin, IGF-1, leucine, estrogens and androgen-precursors may amplify preexistent high mTORC1 signaling due to genetic alterations of the PI3K/PTEN/Akt/Rheb/mTORC1 pathway of PCa cells (Figure 5). Pharmacological mTORC1 inhibitors counteract BCAA, insulin and IGF-1-induced overstimulation of mTORC1 signaling stimulated by the consumption of dairy protein-enriched Western diet
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