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

PLoS One. 2017 Feb 2;12(2):e0171390. doi: 10.1371/journal.pone.0171390. eCollection 2017.

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.

MeSH terms

  • 4-Butyrolactone / analogs & derivatives
  • 4-Butyrolactone / pharmacology
  • Cell Cycle / drug effects
  • Dioxoles / pharmacology
  • Estrogens / pharmacology*
  • Furans / pharmacology
  • Gene Expression Profiling
  • Humans
  • Lignans / pharmacology*
  • MCF-7 Cells / drug effects
  • MCF-7 Cells / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Signal Transduction / drug effects*

Substances

  • Dioxoles
  • Estrogens
  • Furans
  • Lignans
  • matairesinol
  • 2,3-bis(3'-hydroxybenzyl)butane-1,4-diol
  • 4-Butyrolactone
  • sesamin
  • pinoresinol
  • 2,3-bis(3'-hydroxybenzyl)butyrolactone

Grants and funding

This research has been supported partly by a Special Coordination Fund for Promoting Science and Technology (Encouraging Development of Strategic Research Centers), a Knowledge Cluster Initiative program, a grant from Kyushu Sangyo University for promoting basic technologies, and a Grant-in-Aid for Basic Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The funders and Scinet Company provided support in the form of salaries for authors [YZ and KK], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.