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Page 10 Melnik et al. J Transl Genet Genom 2022;6:1-45 https://dx.doi.org/10.20517/jtgg.2021.37

[317]
mTORC1/p70S6K signaling by Raptor phosphorylation , stimulates mTORC1 activation at the
lysosome [318,319] , and induces lipid deposition in HepG2 cells via activation of the mTORC1/S6 kinase 1
[320]
(S6K1)/SREBP-1c pathway .

It has been shown by dynamic microfluidic Raman technology that palmitic acid and arachidonic acid
exhibit a high uptake in PC3 cells, whereas docosahexaenoic acid and eicosapentaenoic acid have inhibitory
[321]
effects on the uptake of palmitic acid and arachidonic acid . The Japan Public Health Center-Based
Prospective Study Group reported relative PCa risks [95% confidence intervals (CI)] on comparison of the
highest with the lowest quartiles of myristic acid and palmitic acid of 1.62 (1.15-2.29) and 1.53 (1.07-2.20),
respectively . A recently published study in the United States including 49,472 men with an average
[322]
follow-up period of 11.2 years and a median total dairy intake of 101 g/1000 kcal showed that regular fat
dairy product intake was associated with late-stage PCa risk (HR = 1.37, 95%CI: 1.04-1.82 comparing the
highest with lowest quartile) and 2% fat milk intake with advanced PCa risk (HR = 1.14, 95%CI: 1.02-1.28
[323]
comparing higher than median intake with no intake group) .

Milk fat globule-EGF factor 8
MFG membrane proteins, predominantly MFG epidermal growth factor 8 (MFG-E8, also known as
lactadherin), stimulates cell proliferation through the PI3K/AKT/mTORC1 signaling pathway [324-327] .
Increased levels of MFG-E8 found in tissue and plasma exosomes from PCa patients have been compared
with controls [327,328] . Notably, M2 polarization of PCa-associated macrophages is induced by MFG-E8-
[329]
mediated efferocytosis . Of note, MFG-E8 is a major constituent of MFG membranes , but it is
[327]
detectable only in minor amounts in milk EVs and exosomes [326-328] . However, MFG-E8 mRNA has been
detected in bovine MEX [329-332] . Remarkably, MFG-E8 promotes the absorption of dietary TAGs and the
[333]
cellular uptake of fatty acids and is linked to obesity . MFG-E8 coordinates fatty acid uptake through αvβ3
integrin- and αvβ5 integrin-dependent phosphorylation of AKT by PI3K and mTOR complex 2, leading to
translocation of CD36 antigen and fatty acid transport protein 1 from cytoplasmic vesicles to the cell
surface . Thus, MFG-E8 plays a key role in the absorption and storage of dietary fats . Recent evidence
[333]
[333]
[334]
indicates that insulin receptor signaling is autoregulated through MFG-E8 and the αvβ5 integrin .
Intriguingly, αvβ5 expression is upregulated in PCa and PCa cells [335,336] , and the differentiation of PCa seems
to influence integrin expression and subcellular distribution . Notably, αvβ5 integrin expression is
[335]
increased in plasma and urine EVs derived from PCa patients . Whole milk, especially milk fat with
[337]
enriched amounts of MFG-E8, may additionally promote PI3K/AKT/mTORC1 signaling in PCa [Figure 2].
Phytanic acid
The lipid fraction of milk contains phytanic acid (3,7,11,15-tetramethyl-hexadecanoic acid) representing
0.7% of milk total long-chain fatty acids . Depending on the intensity of grass feeding, the content of
[338]
phytanic acid varies from 9.7 mg/100 g in whole milk to 200 mg/100 g total milk lipids and represents a
marker of organic milk production [339-341] . Higher phytanic acid intake, although unrelated to the risk of
localized PCa, was associated with increased risks of advanced PCa . It has been demonstrated in rat
[342]
aortic smooth muscle cells that phytanic acid reduces the expression of IGF-1 receptor but increases γ-
secretase activity . Notably, γ-secretase mediates the intramembranous cleavage of CD44 , a major
[343]
[344]
adhesion molecule for the extracellular matrix components that is implicated in a wide variety of
physiological and pathological processes including the regulation of EMT, cancer growth, and
metastasis [345-351] . CD44 intracellular domain (CD44-ICD) acts as a signal transduction molecule
translocating into the nucleus . A strong functional relationship between CD44-ICD and RUNX2 has
[352]
recently been shown in AR-positive PC3 cells . In the nucleus, CD44-ICD and RUNX2 interact, and this
[353]
interaction was higher in PC3 cells transfected with RUNX2 cDNA. In contrast, inhibition of CD44 cleavage