| Summary: | <p>Abstract</p> <p>Background</p> <p>The objective of this study was to investigate whether the levels of glucose or certain amino acids could regulate the expression of a cell cycle repressor protein p27(Kip1), thereby dictating the risk of cancer in either obesity or caloric/dietary restriction. Previously, we identified and reported four different upstream molecular signaling pathways of p27 expression in human breast cancer cells. We called these four pathways as pathway #1, #2, #3 and #4. We found that 4-hydroxytamoxifen - but not tamoxifen - up-regulated the expression of p27 using pathway #1 which consisted mainly of receptor tyrosine kinases and mTORC1. We now investigate, using 4-hydroxytamoxifen as a reference anti-cancer agents, whether (a) the moderate increase in the concentration of <smcaps>D</smcaps>-(+)-glucose could down-regulate and, conversely, (b) the deficiency of <smcaps>D</smcaps>-(+)-glucose or certain <smcaps>L</smcaps>-amino acids could up-regulate the expression of p27 in these cells using pathway #2 which consists mainly of AMPK and mTORC1.</p> <p>Results</p> <p>Using human MDA-MB-231 breast cancer cells <it>in vitro</it>, these hypotheses were tested experimentally by performing p27-luciferase reporter transfection assays and western immunoblot analyses. The results obtained are consistent with these hypotheses. Furthermore, the results indicated that, although 4-hydroxytamoxifen used primarily pathway #1 to down-regulate the phosphorylation of 4E-BP1 and up-regulate the expression of p27, it also secondarily down-regulated the phosphorylation of S6K1. In contrast, the deficiency of <smcaps>D</smcaps>-(+)-glucose or <smcaps>L</smcaps>-leucine used primarily pathway #2 to down-regulate the phosphorylation of S6K1, but they also secondarily down-regulated the phosphorylation of 4E-BP1 and up-regulated the expression of p27. Finally, deficiency of <smcaps>D</smcaps>-(+)-glucose or <smcaps>L</smcaps>-leucine - but not 4-hydroxytamoxifen - up-regulated the expression of mitochondrial ATP5A and SIRT3.</p> <p>Conclusions</p> <p>(a) 4-Hydroxitamoxifen used primarily pathway #1 to up-regulate the expression of p27. (b) Moderate increase in the concentration of <smcaps>D</smcaps>-(+)-glucose used primarily pathway #2 to down-regulate the expression of p27. (c) Deficiency of <smcaps>D</smcaps>-(+)-glucose or <smcaps>L</smcaps>-leucine also used primarily pathway #2 to up-regulate the expression of p27. (d) Deficiency of <smcaps>D</smcaps>-(+)-glucose or <smcaps>L</smcaps>-leucine - but not 4-hydroxytamoxifen - up-regulated the expression of mitochondrial ATP5A in the Complex V of respiratory oxidation-phosphorylation chain and mitochondrial SIRT3. The SIRT3 is one of the seven mammalian anti-aging as well as anti-metabolic sirtuins.</p>
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