Page 105 - Read Online

Page 8 Melnik et al. J Transl Genet Genom 2022;6:1-45 https://dx.doi.org/10.20517/jtgg.2021.37

globule epidermal growth factor 8 (MFG-E8) further enhance PI3K-AKT signaling. miR-21, a prominent
signature miR of cow milk, targets SMAD7, which operates as a crucial inhibitor of RUNX2 expression.
Obviously, milk-derived endocrine and epigenetic signaling promotes PI3K-AKT-mTORC1 signaling and
augments androgen and RUNX2 signaling in PCa.

Growth hormone
Milk consumption enhances GH levels in children and peak GH levels in adults [212,213] . Already two decades
ago, the GH-IGF-1 axis was implicated in prostate carcinogenesis . PCa cells express both GH and GH
[214]
receptor (GHR) [215-217] . As shown in LNCaP cells, GH induces time- and dose-dependent signaling events.
These include phosphorylation of Janus kinase 2, GHR, and signal transducer and activator of transcription
[215]
5, p42/p44 MAPK and AKT, respectively. Furthermore, GH modifies AR expression . In androgen-
[216]
dependent LNCaP cells, estradiol (E2), cortisol, and IGF-1 and IGF-2 all stimulate GH binding . Human
GH promotes IGF and β-E2 receptor (ERβ) gene expressions and interacts with IGF-1 and E2 to stimulate
androgen-dependent LNCaP cell proliferation . Furthermore, exogenous and autocrine GH augments the
[217]
migration and invasion of LNCaP cells, dependent upon PI3K, STAT5, and MEK1/2 pathways .
[218]
In contrast, patients with Laron syndrome, who present dwarfism due to a genetic loss-of-function
mutation of GHR [219,220] , exhibit failures in the GH-GHR-IGF-1 signal transduction process, resulting in
congenital IGF-1 deficiency associated with a reduced incidence of cancers including PCa [221-224] . Notably,
disruption of GH signaling retards early stages of prostate carcinogenesis in the C3(1)/T antigen mouse and
Probasin/TAg rat model [225,226] . GH-releasing hormone receptor antagonists decreased cell viability and
provoked a reduction in proliferation in LNCaP and PC3 cells . Recent evidence indicates that GH
[227]
induction following androgen deprivation therapy or AR inhibition may contribute to the CRPC
[228]
progression by bypassing androgen growth requirements . In fact, GH induces expression of the AR
splice variant 7, which correlates with antiandrogen resistance and induces IGF-1 that is implicated in PCa
[228]
progression and ligand-independent AR activation . Increased GH signaling via milk consumption may
thus promote PCa development and CRPC progression.

Insulin-like growth factor 1
Milk consumption increases circulating IGF-1 levels in children, adolescents, and adults [212,213,229-235] . Whereas
a cross-sectional study in Bavaria of 526 men and women aged 18-80 years showed that only milk but not
[234]
yogurt and cheese intake increased serum IGF-1 levels , a larger British cohort study including 11,815
participants reported that milk and yogurt protein, but not cheese protein, increased serum IGF-1
[235]
[236]
concentrations . Hoppe et al. observed an increase in serum insulin by isolated consumption of whey
protein and an increase of IGF-1 by isolated casein supplementation after seven days in prepubertal boys.
IGF-1 is a component of human and bovine milk [237-239] . Bovine IGF-1 exhibits an identical amino acid
sequence compared to human IGF-1 . The GH-IGF-1 axis is of physiological importance for infant
[240]
growth [241,242] . Of note, it is not the oral uptake of bovine GH and IGF-1 in dairy milk that increases serum
IGF-1 levels, but the induction of hepatic IGF-1 synthesis and release after milk consumption [212,239] .
Tryptophan, a major amino acid enriched in milk proteins, is the precursor of serotonin [5-
hydroxytryptamine (5-HT)], which via 5-HT receptors stimulates hypothalamic GHRH release and
2
pituitary GH secretion, thus increasing serum GH levels . Hepatic GH/GHR signaling is the major
[243]
stimulus increasing circulatory IGF-1 levels [Figure 2] [244,245] .

The milk protein-derived amino acids tryptophan, methionine, and arginine synergistically enhance hepatic
IGF-1 synthesis and secretion [212,246-252] . Exposure to bovine MEX to cultured human colonic LS174T cells