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Table 3. Overactivated PI3K-AKT-mTORC1 signaling in PCa compared to milk signaling
Factor Prostate cancer Ref. Milk-derived signaling Ref.
GH GH and GHR is expressed in PCa tissue; activates PCa cell [215-218,228] Milk consumption increases GH serum levels in children and adults [212,213]
proliferation and PI3K; induces hepatic IGF-1 secretion; induces AR
splice variant 7
IGF-1 Systemically and locally increased in PCa [125-151] Milk-induced IGF-1 increases serum levels in all age groups, component of bovine milk; [212-213,229-235,
activates PI3K-AKT-mTORC1 signaling 237-239]
MFG-E8 Higher expression in PCa and serum exosomes of PCa patients; [327,328] Component of MFG membranes; MFG-E8 mRNA is a cargo of MEX; promotes PI3K- [324-327,329,332]
interacts with αvβ5 integrin AKT-mTORC1 signaling
Estrogens ERα is expressed in PCa and promotes PCa progression; increases [381-385] Increased levels of milk estrogens of permanently pregnant dairy cows, especially [373]
expression of AR and IGF-1 by E1 in PCa cells elevation of E1
miR-148a OncomiR of PCa, correlates with Gleason score; targets the PI3K [97-100,106-110] Most abundant miR of bovine milk and MEX surviving pasteurization; identical with [418,421,436,451,
inhibitor PIK3IP1 increasing PI3K activity; inhibits PTEN and human miR-148a; targets DNMT1; enhances expression of INS, IGF1, and TOR and 454,478,464-467]
DNMT1 expression suppresses AMPK activity
miR-21 Biomarker and oncomiR of PCa progession; inhibits PTEN, FOXO1, [69,70,78-95,456- Signature miR of cow milk and MEX; increases in serum after milk consumption; [420,422,438,451]
and SMAD7 expression; increases RUNX2 expression 458] identical with human miR-21; bovine MEX miR-21 accumulates in peripheral murine
tissues
miR-125b Enhances PCa growth, suppresses p53, the inhibitor of AR and [492-495] Dominant and resistant miR of commercial milk [428,465,481]
mTORC1
miR-30d OncomiR of PCa promoting RUNX2 expression; suppresses p53, [494,498,510,511] Belongs to the top 10 miRs of bovine milk; component of bovine MEX accumulating in [418,436,437,490,
the negative regulator of AR and mTORC1 distant murine tissues afer oral gavage 491]
miR-155 Reduced expression of FBXW7 in PCa [487,488] miR component of cow milk; targets PTEN and FBXW7 and thereby activates mTORC1 [483,484,486]
signaling
miR-223 Reduced expression of FBXW7 in PCa [487,488] miR component of cow milk; targets FBXW7 and attenuates proteasomal mTOR and [485,486]
oncogen degradation
miR-29b Marker of EVs of PCa [524] Dose-dependent increase in serum 6 h after milk consumption; attenuates BCAA [359,517,525]
catabolism via targeting DBT; induces RUNX2 expression
BCAA PCa cells are leucine addicts and increase intracellular leucine [46,49] Compared to other protein sources, whey and casein proteins contain high amounts of [277-298]
content via AR-mediated upregulation of LATs for mTORC1-driven leucine as well as glutamine, critical amino acids activating mTORC1
growth
Palmitic acid PCa cells exhibit high uptake of palmitic acid; palmitic acid intake [321,322] Palmitic acid is the most abundant saturated fatty acid of milk triacylglycerols; palmitic [311,318,319,333]
correlates with PCa risk acid activates mTORC1 at the lysosome; MFG-E8 promotes fatty acid uptake and
deposition
Aflatoxin Rapid uptake of AFB1 in rat and dog prostate [548] Commercial milk is contaminated with aflatoxins; AFM1 levels rise in maize-fed cows [537-541,548]
(M, B1)
mTORC1 Upregulated in PCa; involved in PCa intiation and progression; [57-62,393] Milk via insulin/IGF-1 signaling and milk-derived BCAAs (leucine) activates mTORC1 [20,21,154]
phosphorylation of ERα activating ER target gene expression further augmented by milk-derived miRs, especially miR-148a and miR-21
FoxO1 Inactivated by increased PI3K-AKT signaling, functions as nuclear [41-44,53] Nuclear FoxO1 inactivation by milk consumption via AKT-mediated phosphorylation [609,611]
cosuppressor of AR and nuclear extrusion
Phytanic Associated with PCa risk; increases γ-secretase activity, which [339-342,353,362] Branched-chain fatty acid of milk, increased by organic milk production [339-342]
acid cleaves CD44 that interacts with RUNX2