Submitted on March 20, 2009
Revised on May 6, 2009
Accepted on May 28, 2009
A novel mechanism of natural vitamin E tocotrienol activity: involvement of ER
signal transduction
Raffaella Comitato1*, Kalanithi Nesaretnam2, Guido Leoni3, Roberto Ambra3, Raffaella Canali3, Alessandro Bolli4, Maria Marino PhD5, and Fabio Virgili3
1 National Research Institute for Food and Nutrition (INRAN)
2 bMalaysian Palm Oil Board, 6 Persiaran Institusi
3 INRAN
4 Università roma 3
5 University ROMA TRE
* To whom correspondence should be addressed. E-mail: rcomitato{at}hotmail.com.
Vitamin E is a generic term used to indicate all tocopherol (TOC) and tocotrienol (TT) derivates. In the last years, several papers have shown that a TTs-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 TTs action is still unclear. In the present study, we propose, for the first time, a novel mechanism for TTs activity that involves estrogen receptor (ER) signaling. In silico simulations and in vitro binding analyses indicate an high affinity of TTs for ER
but not for ER
. In addition, in ER-containing MDA-MB-231 breast cancer cells we demonstrate that TTs increase the ER translocation into the nucleus which, in turn, activates estrogen responsive genes (MIC-1, EGR-1 and Cathepsin D) as demonstrated by cell pre-incubation with the ER inhibitor, ICI 182.780. Finally, we observe that TTs treatment is associated with alteration of cell morphology, DNA fragmentation and caspase-3 activation. All together these experiments elucidate the molecular mechanism underling 
- and 
-tocotrienol effects.
