Abstract
Tocopherylquinone (TQ), the oxidation product of alpha-tocopherol (AT), is a bioactive molecule with distinct properties from AT. In this study, AT and TQ are investigated for their comparative effects on growth and androgenic activity in prostate cancer cells. TQ potently inhibited the growth of androgen-responsive prostate cancer cell lines (e.g., LAPC4 and LNCaP cells), whereas the growth of androgen-independent prostate cancer cells (e.g., DU145 cells) was not affected by TQ. Due to the growth inhibitory effects induced by TQ on androgen-responsive cells, the anti-androgenic properties of TQ were examined. TQ inhibited the androgen-induced activation of an androgen-responsive reporter and inhibited the release of prostate specific antigen from LNCaP cells. TQ pretreatment was also found to inhibit AR activation as measured using the Multifunctional Androgen Receptor Screening assay. Furthermore, TQ decreased androgen-responsive gene expression, including TM4SF1, KLK2, and PSA over 5-fold, whereas AT did not affect the expression of androgen-responsive genes. Of importance, the antiandrogenic effects of TQ on prostate cancer cells were found to result from androgen receptor protein down-regulation produced by TQ that was not observed with AT treatment. Moreover, none of the androgenic endpoints assessed were affected by AT. The down-regulation of androgen receptor protein by TQ was abrogated by co-treatment with antioxidants. Overall, the biological actions of TQ were found to be distinct from AT, where TQ was found to be a potent inhibitor of cell growth and androgenic activity in androgen-responsive prostate cancer cells.
Highlights
The role of antioxidant action in cancer development and progression is unclear
Vitamin E is a family of naturally occurring dietary factors (e.g., α,β,γ,δ-tocopherols and -tocotrienols) with a major biologically active form recognized as RRR-α-tocopherol (RRR-AT) [1,2]. αtocopherol (AT) acts primarily as an antioxidant, reducing cellular oxidative damage produced by oxidized lipids [1,2]
To determine if the inhibition of cell growth by TQ was in part due to effects on cell viability, DU145, LAPC4 and LNCaP cell viability was measured by hemocytometry and trypan blue exclusion
Summary
The role of antioxidant action in cancer development and progression is unclear. Vitamin E is a family of naturally occurring dietary factors (e.g., α-,β-,γ-,δ-tocopherols and -tocotrienols) with a major biologically active form recognized as RRR-α-tocopherol (RRR-AT) [1,2]. Αtocopherol (AT) acts primarily as an antioxidant, reducing cellular oxidative damage produced by oxidized lipids [1,2]. The major oxidation product of AT is α-tocopherylquinone (TQ), which is formed by the two-electron oxidation of the chromanol moiety of AT (Fig 1). TQ has been shown to inhibit the growth of colon cancer cells, whereas AT was not observed to alter the growth of these cells [4]. TQ is established as a bioactive quinone for some cancers, its action on prostate cancer cell growth and androgenic pathways in prostate cancer cells are unknown
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