Alpha tocopherol transfer protein (αTTP) is expressed in endometrial carcinoma and is correlated with FIGO stage and 5-year survival.

BACKGROUND: Increased oxidative stress plays an important role in cancer development. Vitamin E is considered a potent anti-oxidant and its transfer protein αTTP facilitates its cellular delivery. We hypothesize that αTTP could be present in and have an impact on endometrial cancer. MATERIALS AND METHODS: Ishikawa endometrial cancer cells were treated with BSO and AAPH to mimick oxidative stress conditions. αTTP was detected by immunocytochemistry and western blot. αΤΤP expression was then assessed in 191 endometrioid endometrial carcinomas. Immunopositivity was correlated with grade, FIGO stage, and 5-year survival. Immuno-reactivity was assessed with a semi-quantitative score. RESULTS: AAPH- and BSO-induced αTTP expression in Ishikawa cells. Immunohistochemical assessment of the 191 endometrial cancer cases showed that αTTP expression correlated with FIGO stage (p = 0.014) but not with grade. Five-year survival was significantly better in cases of lower αTTP expression compared to cases with higher expression (p = 0.041). CONCLUSIONS: The current results show that αTTP plays a role in endometrial carcinoma. Possibly endometrial cancer cells attempt to protect themselves from increasing oxidative stress by up-regulating αTTP. Selective molecular interventions targeting oxidative stress escape strategies, e.g., by overexpression of αTTP, could, therefore, allow oxidative stress to damage cancer cell membranes and thus restrict cancer progression.

Oxidative stress stimulates α-tocopherol transfer protein in human trophoblast tumor cells BeWo.

α-Tocopherol transfer protein (α-TTP) has been identified as the major intracellular transport protein for the antioxidant vitamin E (α-tocopherol). Expression of α-TTP on the reproductive system has been described both in mouse uterus and lately in the human placenta. The aim of this study was to clarify if placental expression of α-TTP can be modified by substances causing oxidative reactions. The human choriocarcinoma cell line BeWo was, therefore, treated with two known pro-oxidants. α-TTP expression was determined with immunocytochemistry and evaluated by applying a semiquantitative score. The presence of pro-oxidants in BeWo cells induced α-TTP expression. We thus hypothesize that stimulation of α-TTP expression by oxidative stress, as this was induced by pro-oxidants, could be part of an antioxidant process occurring in the placenta in the aim of enhancing the supply of α-tocopherol. This process could occur both in normal pregnancies, as well as in pregnancy disorders presented with intensified oxidative stress. In that view, this model is proposed for further oxidative stress studies on trophoblast and placenta, on the grounds of clarifying the role of α-tocopherol in pregnancy physiology and pathophysiology.

Immunohistochemical localization of alpha-tocopherol transfer protein and lipoperoxidation products in human first-trimester and term placenta.

OBJECTIVE: Pregnancy is described as a state of oxidative stress arising from the high metabolic turnover taking place during feto-placental development and little is known about the balance of oxidation and antioxidation in early human pregnancy. The aim of this study was to analyze placental expression of alpha-tocopherol transfer protein (alpha-TTP) as the major transport protein for the antioxidant alpha-tocopherol as well as the placental expression of two lipoperoxidation products, malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE) in early first-trimester and term human placenta. STUDY DESIGN: Placental tissue was obtained from 10 pregnancy interruptions at 6-8 weeks gestational age and 10 samples were obtained from term pregnancies after routine cesarean section. The placental expression of alpha-TTP, MDA and HNE has been investigated with immunohistochemistry by the use of specific human alpha-TTP, MDA and HNE antibodies. RESULTS: While MDA and HNE showed similar expression in first-trimester and term placenta, alpha-TTP expression was less in first-trimester syncytiotrophoblast as compared to term. In first-trimester specimen, alpha-TTP showed major expression in extravillous trophoblast. In amniotic epithelial cells, a rising tendency in all three parameters investigated from immature to mature cells could be documented. No direct correlation between alpha-TTP, MDA and HNE expression was detected. CONCLUSIONS: Our study shows the presence of alpha-TTP not only in term, but in first-trimester extravillous trophoblast, syncytiotrophoblast and amniotic epithelium. Furthermore, lipoperoxidation products MDA and HNE are also present in first-trimester and term placenta, documenting the presence of oxidative processes in the placenta from early on. It therefore seems possible that scavenging of reactive oxygen species (ROS) by alpha-tocopherol is already required in first-trimester human pregnancy, but the missing correlation to MDA and HNE expression leads to the speculation that alpha-TTP and its ligand alpha-tocopherol have functions beyond the antioxidative capacity of alpha-tocopherol in early pregnancy.