Whole flaxseed diet alters estrogen metabolism to promote 2-methoxtestradiol-induced apoptosis in hen ovarian cancer

J Nutr Biochem. 2017 Apr;42:117-125. doi: 10.1016/j.jnutbio.2017.01.002. Epub 2017 Jan 23.

Abstract

The study reported here demonstrates that a flaxseed-supplemented diet causes ovarian tumors in the laying hen to undergo apoptosis, resulting in a reduction of tumor burden, reducing the frequency and severity of ovarian cancer. We have previously shown in normal ovaries that flaxseed and its components down-regulate ERalpha and alter the expression of enzymes that metabolize estrogen. In this study, we analyzed the effects of the two main components of whole flaxseed, ligan and omega 3 fatty acids on estrogen metabolism and the estrogen receptor in ovarian tumors. ER alpha expression was up-regulated in the ovarian tumors and was not affected by diet. Liver CYP1A1 expression was significantly increased by the whole flaxseed diet with a corresponding increase in 2-methoxyestradiol plasma levels. We also observed increased p38 and ERK 1/2 MAPK activation in the ovary as well as an increase in apoptosis in the tumor epithelium. SMAD 7, a factor involved in the 2-methoxyestradiol-mediated apoptosis pathway was also up-regulated in tumors from the whole flaxseed diet group. 2-methoxyestradiol-induced antitumor effects were further validated by in human ovarian cancer cells. This study details the effect of flaxseed diet on estrogen metabolism and demonstrates the antiovarian cancer effects of 2-methoxyestradiol.

Keywords: 2-Methoxtestradiol; Apoptosis; Estrogen metabolism; Flaxseed; Ovarian cancer.

MeSH terms

  • 2-Methoxyestradiol
  • Animals
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Chickens
  • Cytochrome P-450 CYP1B1 / metabolism
  • Cytochrome P-450 CYP3A / metabolism
  • Dietary Supplements
  • Estradiol / analogs & derivatives
  • Estradiol / metabolism
  • Estradiol / toxicity
  • Estrogen Receptor alpha / metabolism
  • Female
  • Flax*
  • Humans
  • Ovarian Neoplasms / chemically induced
  • Ovarian Neoplasms / diet therapy*
  • Ovarian Neoplasms / pathology
  • Ovary / metabolism*
  • Smad7 Protein / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Estrogen Receptor alpha
  • Smad7 Protein
  • Estradiol
  • 2-Methoxyestradiol
  • Cytochrome P-450 CYP1B1
  • Cytochrome P-450 CYP3A
  • p38 Mitogen-Activated Protein Kinases
  • Caspase 3