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

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 alpha- and gamma-tocopherol as inducers. Effects of alpha- and gamma-tocopherol on the cell cycle, proliferation and differentiation, were examined. A more significant growth inhibition activity for gamma- than for alpha-tocopherol was observed. Flow cytometry analysis of alpha- and gamma-tocopherol-treated prostate carcinoma PC3 cells showed decreased progression into the S-phase. This effect, particularly evident for gamma-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 gamma-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 gamma-form of vitamin E as a differentiative agent, in combination with the common cytotoxic treatments for prostate cancer therapy.