Δ-Tocopherol inhibits the development of prostate adenocarcinoma in prostate specific Pten−/− mice. (7th November 2017) - Wang, Hong
Abstract : By feeding prostate-specific Pten−/− mice an AIN93M, a 0.2% α-T or a 0.2% δ-T supplemented diet, we found δ-T reduced prostate adenocarcinoma multiplicity. δ-T-specific cancer preventive activity is mediated through its inhibition of the AKT activation, beyond its antioxidant activity. Abstract: The PTEN/PI3K/AKT axis plays a critical role in regulating cell growth, differentiation and survival. Activation of this signaling pathway is frequently found in human cancers. Our previous studies demonstrated that δ-tocopherol (δ-T) attenuates the activation of AKT by growth factor in prostate cancer cell lines, leading to inhibition of proliferation and induction of apoptosis. Herein, we investigated whether δ-T inhibits the development of prostate adenocarcinoma in prostate-specific Pten−/− (Pten p−/− ) mice in which the activation of AKT is the major driving force for tumorigenesis. By feeding Pten p−/− mice with AIN93M or 0.2% δ-T supplemented diet starting at the age of 6 or 12 weeks, we found that δ-T treatment reduced prostate adenocarcinoma multiplicity at the age of 40 weeks by 53.3 and 42.7%, respectively. Immunohistochemical (IHC) analysis demonstrated that the phosphorylation of AKT (T308) was reduced in the prostate of the mice administered the δ-T diet. Consistently, proliferation was reduced and apoptosis was increased in prostate lesions of mice on the δ-T diet. Oxidative stress, as determined by IHC staining of 8-OH-dG, was not altered during prostate tumorigenesis, nor was it affected by administration of δ-T. In contrast, α-tocopherol (α-T) at 0.2% in the diet did not affect prostate adenocarcinoma multiplicity in the Pten p−/− mice. This finding is consistent with data from our previous study that δ-T, but not α-T, inhibits the activation of AKT and the growth of prostate cancer cells. Together, these results demonstrate that δ-T inhibits the development of prostate adenocarcinoma in Pten p−/− mice, mainly through inhibition of AKT activation.