Differential and directional estrogenic signaling pathways induced by enterolignans and their precursors

Abstract

Mammalian lignans or enterolignans are metabolites of plant lignans, an important category of phytochemicals. Although they are known to be associated with estrogenic activity, cell signaling pathways leading to specific cell functions, and especially the differences among lignans, have not been explored. We examined the estrogenic activity of enterolignans and their precursor plant lignans and cell signaling pathways for some cell functions, cell cycle and chemokine secretion. We used DNA microarray-based gene expression profiling in human breast cancer MCF-7 cells to examine the similarities, as well as the differences, among enterolignans, enterolactone and enterodiol, and their precursors, matairesinol, pinoresinol and sesamin. The profiles showed moderate to high levels of correlation (R values: 0.44 to 0.81) with that of estrogen (17β-estradiol or E2). Significant correlations were observed among lignans (R values: 0.77 to 0.97), and the correlations were higher for cell functions related to enzymes, signaling, proliferation and transport. All the enterolignans/precursors examined showed activation of the Erk1/2 and PI3K/Akt pathways, indicating the involvement of rapid signaling through the non-genomic estrogen signaling pathway. However, when their effects on specific cell functions, cell cycle progression and chemokine (MCP-1) secretion were examined, positive effects were observed only for enterolactone, suggesting that signals are given in certain directions at a position closer to cell functions. We hypothesized that, while estrogen signaling is initiated by the enterolignans/precursors examined, their signals are differentially and directionally modulated later in the pathways, resulting in the differences at the cell function level.

MicroRNA as Crucial Regulators of Gene Expression in Estradiol-Treated Human Endothelial Cells

“…Control cells were exposed to the same vehicle of cells treated with E2 (0.1% etanol) or antagonist (0.1% DMSO). All concentrations and times selected were chosen taking into account previous studies [5,19,20]. A schematic workflow of the experimental design is provided in Fig.…”

Effect of Dietary Flaxseed Intake on Circulating Sex Hormone Levels among Postmenopausal Women: A Randomized Controlled Intervention Trial

“…Our finding of a stronger correlation with enterolactone than enterodiol may be explained by the shorter half-life of enterodiol, which is further metabolized into enterolactone (7,8). Additionally, in vitro and in vivo studies have demonstrated differential effects of enterolactone and enterodiol on estrogenrelated pathways in cancer development (54)(55)(56).…”

The Microbiome–Estrogen Connection and Breast Cancer Risk

“…Over the decades, many studies have supported the estrobolome hypothesis ( Figure 2) [12][13][14][15][16]19,[21][22][23][24][25][26][27][28][29][30][31][32][33][34]. Germfree rats excrete unquantifiable amounts of hormones whereas conventional rats, under the same conditions, excrete significant amount of free steroid hormones measurable by gas chromatography and mass spectrometry [33].…”

“…In addition to metabolizing estrogens, enteric microbes perform a very important role in synthesis of estrogen-like compounds or estrogen mimics from dietary sources [27,32,[48][49][50][51][52]. Phytoestrogens are group of plant compounds containing one to two benzene ring and two or three hydroxyl groups, similar to 17β-estradiol in structure and molecular weight [53].…”

“…Plant-based lignans are present in high concentrations in soy, flax seeds, and sesame, and to some extent in fruits, vegetables, and berries [52]. These lignans are converted into compounds like enterodiol, enterolactone, sesamin, matairesinol, and pinoresinol [27,32]. Enterolactone is produced by the action of Eggerthella [55].…”