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Genistein Regulates Ceramide Metabolism by Inducing Acid Ceramidase Expression in MCF‐7 Breast Cancer Cells
Author(s) -
Lucki Natasha Chrystman,
Sewer Marion B
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.694.11
Subject(s) - sphingosine , ceramide , sphingolipid , cell growth , microbiology and biotechnology , estrogen receptor , chemistry , apoptosis , biology , sphingosine 1 phosphate , cancer research , receptor , biochemistry , cancer , breast cancer , genetics
Aberrant estrogen receptor (ERα) expression plays a role in the pathogenesis of most breast cancers. Genistein (gen) is a major isoflavone that stimulates tumor growth by inducing the transcription of many estradiol (E2)‐sensitive genes. Conversely, micromolar concentrations of gen inhibit cell growth and induce apoptosis. Ceramide (cer) and sphingosine‐1‐phosphate (S1P) have been extensively studied for their opposing roles in cancer pathogenesis. Cer inhibits cell growth and promotes apoptosis while S1P is a potent modulator of cell proliferation. Acid ceramidase (ASAH1) directly regulates the concentrations of these bioactive molecules by hydrolyzing cer to form sphingosine, which is phosphorylated into S1P. Based on the critical role that the cer/S1P rheostat plays in regulating cellular homeostasis, we hypothesized that gen modulates sphingolipid metabolism by controlling the expression of ASAH1. We show that 20 nM gen induces ASAH1 mRNA and protein expression by 4.2‐ and 2.3‐fold, respectively, concomitant with an increase in ceramidase activity. Reporter gene deletion studies localized the gen‐responsive region to within 500 bp of the transcription start site. In addition, EMSA and ChIP studies revealed that ERα binds to the gen‐responsive region of the ASAH1 promoter. Our results reveal a novel mechanism through which gen promotes cell proliferation, by activating cer metabolism.