γ-Tocopherol inhibits human prostate cancer cell proliferation by up-regulation of transglutaminase 2 and down-regulation of cyclins

Abstract

To establish a system to study differentiation therapy drugs, we used the androgen-independent human prostate PC-3 tumor cell line as a target and α- and γ-tocopherol as inducers. Effects of α- and γ-tocopherol on the cell cycle, proliferation and differentiation, were examined. A more significant growth inhibition activity for γ- than for α-tocopherol was observed. Flow cytometry analysis of α- and γ-tocopherol-treated prostate carcinoma PC3 cells showed decreased progression into the S-phase. This effect, particularly evident for γ-tocopherol, was associated with an up-regulation and increased activity of transglutaminase 2 (TG2), a reduced DNA synthesis and a remarkable decreased levels of cyclin D1 and cyclin E. Activation of TG2 suggests that γ-tocopherol has an evident differentiative capacity on PC3 cells, leading to an increased expression of TG2, and reduced cyclin D1 and cyclin E levels, affecting cell cycle progression. It is feasible that up-regulation and activation of TG2, associated with a reduced proliferation, are parts of a large-scale reprogramming that can attenuate the malignant phenotype of PC3 cells in vitro. These data suggest further investigation on the potential use of this γ-form of vitamin E as a differentiative agent, in combination with the common cytotoxic treatments for prostate cancer therapy.

Vitamin E: A dark horse at the crossroad of cancer management

“…γ-tocopherol exhibited greater potency including increased expression and activity of transglutaminase 2 , a cell differentiation marker that induces differentiation and eventual apoptosis. Given that γ-tocopherol is more readily metabolized into γ-carboxyethyl hydroxychroman and previous studies with tocopherol metabolites have shown similar results, it is possible that γ-tocopherol metabolites may be the effector agent resulting in growth inhibition of PC-3 cells, although other studies suggest metabolite formation is largely a detoxification mechanism with little or no effect on proliferation [66–69]. Tocotrienols were consistently more potent at inhibiting cell growth and inducing apoptosis in mouse mammary epithelial cells, CL-S1 when compared to tocopherols [70].…”

“…It is important not to disregard other members of the vitamin E family as well since there are studies indicating γ-tocopherol, the second most common vitamin E isoform could be a beneficial micronutrient. Further, vitamin E transport proteins could prove to be key factors in determining the efficacious property of vitamin E [66–67]. …”

“…A promising study by Torricelli et al, showed that tocopherols affect cell function beyond a mere antioxidant mechanism [66]. Prostate Cancer-3 (PC-3) cells are cells derived from a patient with grade IV androgen independent metastatic prostate cancer and are frequently used in cell culture models.…”

“…It should not be expected that all isoforms are created equal as some studies suggest. Depending on the system studied there exist opposing effects amongst the various vitamin E isoforms [16–17]. Studies indicate that the natural vitamin E isoform RRR -α-tocopherol is preferentially incorporated in lipoproteins and maintained in plasma [18–20], while all other stereo and iso-forms are quickly eliminated through excretion and metabolite formation [21,22].…”

Dietary Total Antioxidant Capacity is Inversely Associated with Prostate Cancer Aggressiveness in a Population-Based Study

“…A similar finding was observed in the ATBC study (35). γ-Tocopherol has been shown to promote apoptosis (36) and inhibit growth (37) in prostate cancer cell lines. Similarly with vitamin E, studies on β-carotene have reported inverse (38–40) or positive (29) associations, and null associations with β-carotene or other carotenoids (41–46).…”