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Am J Physiol Endocrinol Metab 297: E427-E437, 2009. First published June 2, 2009; doi:10.1152/ajpendo.00187.2009
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A novel mechanism of natural vitamin E tocotrienol activity: involvement of ERβ signal transduction

Raffaella Comitato,1,* Kalanithi Nesaretnam,2,* Guido Leoni,1 Roberto Ambra,1 Raffaella Canali,1 Alessandro Bolli,3 Maria Marino,3 and Fabio Virgili1

1National Research Institute for Food and Nutrition, Rome, Italy; 2Malaysian Palm Oil Board, Selangor, Malaysia; and 3Department of Biology, University Roma Tre, Rome, Italy

Submitted 20 March 2009 ; accepted in final form 28 May 2009

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 ERβ but not for ER{alpha}. In addition, in ERβ-containing MDA-MB-231 breast cancer cells, we demonstrated that TTs increase the ERβ 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.

estrogen receptor-β; breast cancer; apoptosis; tocopherol; nuclear receptor


Address for reprint requests and other correspondence: R. Comitato, National Research Institute for Food and Nutrition, via Ardeatina 546, 00178 Rome, Italy (e-mail: comitato{at}inran.it)






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