A novel mechanism of natural vitamin E tocotrienol activity: involvement of ERbeta signal transduction

Raffaella Comitato, Kalanithi Nesaretnam, Guido Leoni, Roberto Ambra, Raffaella Canali, Alessandro Bolli, Maria Marino, Fabio Virgili, Raffaella Comitato, Kalanithi Nesaretnam, Guido Leoni, Roberto Ambra, Raffaella Canali, Alessandro Bolli, Maria Marino, Fabio Virgili

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.

Source: PubMed

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