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: Raffaella Comitato, Kalanithi Nesaretnam, Guido Leoni, Roberto Ambra, Raffaella Canali, Alessandro Bolli, Maria Marino, Fabio Virgili
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 297 Issue 2 Pg. E427-37 (Aug 2009) ISSN: 1522-1555 [Electronic] United States
• PMID: 19491296 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Estrogen Antagonists
• Estrogen Receptor beta
• Ligands
• Tocotrienols
• Fulvestrant
• Estradiol
• Tocopherols

Topics

• Apoptosis (drug effects)
• Computer Simulation
• Estradiol (analogs & derivatives, metabolism, pharmacology)
• Estrogen Antagonists (metabolism, pharmacology)
• Estrogen Receptor beta (agonists, antagonists & inhibitors, chemistry, physiology)
• Fulvestrant
• Humans
• Ligands
• Models, Molecular
• Protein Binding
• Protein Conformation
• Signal Transduction (drug effects, physiology)
• Tocopherols (pharmacology)
• Tocotrienols (metabolism, pharmacology)
• Transcriptional Activation (drug effects)
• Tumor Cells, Cultured