title: Normal human immune cells are sensitive to telomerase inhibition by Brassica-derived 3,3-diindolylmethane,partly mediated via ERα/β-AP1 signaling.
abstract: Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) from Brassica plants are regarded as promising anticancer phytochemicals. The enzyme telomerase is a very attractive target for cancer therapeutics; in normal cells such as lymphocytes, it plays a decisive role for cell maintenance. The effect of I3C and DIM on telomerase in normal human immune cells (PBMC) was studied compared to leukaemia cells (HL-60). Signalling of telomerase regulation via estrogen receptor (ER) was addressed.
  
  
  
  Short-term treatment with I3C and DIM inhibited telomerase activity in leukaemia cells (>30 μM I3C; >3 μM DIM). In CD3/CD28 activated PBMC, inhibition was stronger, though (>3 μM I3C; >1 μM DIM). DIM long-term treatment resulted in DNA damage induction and proliferation inhibition in PBMC as determined by the comet assay and CFSE staining, respectively. A relevance of ERα/β-AP1 signaling for telomerase inhibition on enzyme activity, but not transcription level became evident indicating a nonclassical mode for ER regulation of telomerase by DIM.
  
  
  
  Although desired in cancer cells, this study identified a potential adverse impact of I3C and DIM on telomerase action in normal human immune cells, partly mediated by an ER-dependent mechanism. These new findings should be considered for potential chronic high-dose chemoprevention strategies using these compounds.
authors.affiliation: Molecular Preventive Medicine, Institute of Prevention and Cancer Epidemiology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Herz
authors.affiliation: Molecular Preventive Medicine, Institute of Prevention and Cancer Epidemiology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Hoai Thi Thu
authors.initials: HTT
authors.lastname: Tran
authors.affiliation: Institute of Environmental Health Sciences, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Landerer
authors.affiliation: Molecular Preventive Medicine, Institute of Prevention and Cancer Epidemiology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Gaus
authors.affiliation: Molecular Preventive Medicine, Institute of Prevention and Cancer Epidemiology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Schlotz
authors.affiliation: Molecular Preventive Medicine, Institute of Prevention and Cancer Epidemiology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Lia
authors.initials: L
authors.lastname: Lehr
authors.affiliation: Department of Obstetrics & Gynecology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Wolfgang R
authors.initials: WR
authors.lastname: Schäfer
authors.affiliation: Department of Gynecology and Obstetrics, University Medical Center Regensburg, Regensburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Treeck
authors.affiliation: Molecular Preventive Medicine, Institute of Prevention and Cancer Epidemiology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Grace Akinyi
authors.initials: GA
authors.lastname: Odongo
authors.affiliation: Molecular Preventive Medicine, Institute of Prevention and Cancer Epidemiology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Ivan
authors.initials: I
authors.lastname: Skatchkov
authors.affiliation: Molecular Preventive Medicine, Institute of Prevention and Cancer Epidemiology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Lamy
mesh_terms: D001937:Brassica / Q000737:chemistry*; D004249:DNA Damage; D047628:Estrogen Receptor alpha / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000502:physiology*; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D019098:Telomerase / Q000037:antagonists & inhibitors*; D018808:Transcription Factor AP-1 / Q000502:physiology*
chemical_list: C000600034:ESR2 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007211:Indoles; D018808:Transcription Factor AP-1; C016517:indole-3-carbinol; D019098:Telomerase; C016392:3,3'-diindolylmethane
keywords: 3,3-diindolylmethane; ER-AP-1 signal transduction; Phytoestrogens; Safety of phytochemicals; Telomerase