title: A novel mechanism of natural vitamin E tocotrienol activity: involvement of ERbeta signal transduction.
abstract: Vitamin E is a generic term used to indicate all tocopherol (TOC) and tocotrienol (TT) derivates. In the last few years, several papers have shown that a TT-rich fraction (TTRF) extracted from palm oil inhibits proliferation and induces apoptosis in a large number of cancer cells. However, the molecular mechanism(s) involved in TT action is still unclear. In the present study, we proposed for the first time a novel mechanism for TT activity that involves estrogen receptor (ER) signaling. In silico simulations and in vitro binding analyses indicated a high affinity of TTs for ERbeta but not for ERalpha. In addition, in ERbeta-containing MDA-MB-231 breast cancer cells, we demonstrated that TTs increase the ERbeta translocation into the nucleus, which in turn activates estrogen-responsive genes (MIC-1, EGR-1 and cathepsin D), as demonstrated by cell preincubation with the ER inhibitor ICI-182,780. Finally, we observed that TT treatment is associated with alteration of cell morphology, DNA fragmentation, and caspase-3 activation. Altogether, these experiments elucidated the molecular mechanism underling gamma- and delta-TT effects.
authors.affiliation: National Research Institute for Food and Nutrition, 00178 Rome, Italy. comitato@inran.it
authors.forename: Raffaella
authors.initials: R
authors.lastname: Comitato
authors.forename: Kalanithi
authors.initials: K
authors.lastname: Nesaretnam
authors.forename: Guido
authors.initials: G
authors.lastname: Leoni
authors.forename: Roberto
authors.initials: R
authors.lastname: Ambra
authors.forename: Raffaella
authors.initials: R
authors.lastname: Canali
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bolli
authors.forename: Maria
authors.initials: M
authors.lastname: Marino
authors.forename: Fabio
authors.initials: F
authors.lastname: Virgili
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D003198:Computer Simulation; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000378:metabolism / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D000077267:Fulvestrant; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D024505:Tocopherols / Q000494:pharmacology; D024508:Tocotrienols / Q000378:metabolism / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D004965:Estrogen Antagonists; D047629:Estrogen Receptor beta; D008024:Ligands; D024508:Tocotrienols; D000077267:Fulvestrant; D004958:Estradiol; D024505:Tocopherols