Molecular and Biochemical Analysis of the Estrogenic and Proliferative Properties of Vitamin E Compounds

Abstract

Tocols are vitamin E compounds that include tocopherols (TPs) and tocotrienols (TTs). These lipophilic compounds are phenolic antioxidants and are reportedly able to modulate estrogen receptor β (ERβ). We investigated the molecular determinants that control their estrogenicity and effects on the proliferation of breast cancer cells. Docking experiments highlighted the importance of the tocol phenolic groups for their interaction with the ERs. Binding experiments confirmed that they directly interact with both ERα and ERβ with their isoforms showing potencies in the following order: δ-tocols > γ-tocols > α-tocols. We also found that tocols activated the transcription of an estrogen-responsive reporter gene that had been stably transfected into cells expressing either ERα or ERβ. The role of the phenolic group in tocol–ER interaction was further established using δ-tocopherylquinone, the oxidized form of δ-TP, which had no ER affinity and did not induce ER-dependent transcriptional modulation. Tocol activity also required the AF1 transactivation domain of ER. We found that both δ-TP and δ-TT stimulated the expression of endogenous ER-dependent genes. However, whereas δ-TP induced the proliferation of ER-positive breast cancer cells but not ER-negative breast cancer cells, δ-TT inhibited the proliferation of both ER-positive and ER-negative breast cancer cells. These effects of δ-TT were found to act through the down regulation of HMG-CoA reductase (HMGR) activity, establishing that ERs are not involved in this effect. Altogether, these data show that the reduced form of δ-TP has estrogenic properties which are lost when it is oxidized, highlighting the importance of the redox status in its estrogenicity. Moreover, we have shown that δ-TT has antiproliferative effects on breast cancer cells independently of their ER status through the inhibition of HMGR. These data clearly show that TPs can be discriminated from TTs according to their structure.

Dendrogenin A drives LXR to trigger lethal autophagy in cancers

“…The minimized coordinates of the receptor were then used as the starting point for 100 ps at 300k using the Verlet algorithm whereas the constraint used during minimization was maintained. The resulting conformation was then further minimized using 250 steps of the steepest descent followed by a conjugated gradient until the root mean square gradient was less than 0.001 kcal/mol/Å, as was previously done for estrogen receptors 63 , 64 .…”

Alpha-Tocopherol Serum Levels Are Increased in Caucasian Women with Uterine Fibroids: A Pilot Study

“…There are several different antioxidant systems, e.g., enzymes, such as the abovementioned catalase and superoxide dismutase, but there are also dietary antioxidants, like vitamins A, C, or E [ 28 ]. Vitamin E is a collective name for a group of different compounds which include tocopherols (with saturated isoprenoid chain) and tocotrienols (with unsaturated isoprenoid chain) [ 29 , 30 ]. Vitamin E was first characterized in wheat germ oil and lettuce in 1922 [ 30 ].…”

“…Vitamin E is a collective name for a group of different compounds which include tocopherols (with saturated isoprenoid chain) and tocotrienols (with unsaturated isoprenoid chain) [ 29 , 30 ]. Vitamin E was first characterized in wheat germ oil and lettuce in 1922 [ 30 ]. Tocopherols can be found also in corn oil, soybean oil, margarine, sunflower, or safflower oils [ 31 ].…”

Introductory Chapter: Gene Expression Controlling System and Its Application to Medical Sciences

“…The GGAA-containing motif and the GC-box have been suggested to play an essential role in the response. Vitamin E and the related compounds, including tocotrienols, activate transcription by binding to estrogen receptors [57] but inactivate NF-κB activity [58]. Curcumin, which is a diferuloylmethane from the Indian spice turmeric, also targets NF-κB and AP1 to affect survival and proliferation of cells [59], might be applied on the suppression of the APP and the beta-site APP cleaving enzyme 1-encoding BACE1 gene expression [60].…”