The impact of cow's milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer

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.

Acne: Risk Indicator for Increased Body Mass Index and Insulin Resistance

“…The growth-promoting signalling system of milk may not only over-activate mTORC1-driven growth of sebaceous glands but may also affect mTORC1-mediated prostate morphogenesis and maturation during puberty (37). There is convincing evidence from molecular oncology that increased mTORC1 signalling steers cancer initiation and metastasis (38).…”

“…It is thus of concern that epidemiological evidence from Island emphasised an association between daily milk consumption during adolescence and increased risk for advanced prostate cancer later in life (39). Again, the time of puberty, which is associated with the highest incidence of acne, appears to be a most sensitive period affecting long-term prostatic tissue homeostasis (37).…”

“…Western diet, the maximised form of Neolithic nutrition, with highly over-activated mTORC1-signalling appears to promote a special human phenotype, the "milk giant" characterised by increased linear growth (40), increased BMI, obesity (10,20,21), frequent juvenile-onset myopia (increased vitreal chamber growth) (41), insulin resistance (23), type 2 diabetes and cancer (37,(42)(43)(44). This "maximised" growth phenotype exhibits a high prevalence of acne, a proposed indicator of exaggerated mTORC1-signalling.…”

Effect of Concurrent Training and Supplementation with β-Hydroxy- β-Methylbutyirate (HMB) on the Prostate: Alterations in the Androgen Receptor and Inflammation

“…The mTORC induced by HMB links amino acids, growth factors, and energy availability to prostate epithelial cell growth, proliferation, motility, autophagy, morphogenesis, and tumorigenesis (Melnik et al, 2012). HMB supplementation increased the number of mast cells in the prostate, and increased stromal and acinar inflammation.…”

Modelagem e simulação dinâmica da pasteurização contínua de leite sujeito à incrustação.

“…células somáticas e pigmentos (DAMODARAN et al, 2007;HARDING, 1995;LIMA, 2010;MELNIK et al, 2012;SCHUKKEN et al, 2003;SOUZA et al, 2009). …”