Resveratrol Modulates the Expression of PTGS2 and Cellular Proliferation in the Normal Rat Endometrium in an AKT-Dependent Manner

Resveratrol (trans-3,4N-trihydroxystilbene), a phytoalexin present in grapes and red wine is emerging as a natural compound with anticancer properties. However, the physiological and molecular effects of resveratrol on normal uterine cells are poorly understood. In the present study we evaluated the effects of resveratrol on normal uterine cells and the mechanisms involved in vivo. Healthy immature rats were treated s.c. with resveratrol (0, 0.5, 5, and 50 mg/kg body weight) for 7 consecutive days and euthanized on the eighth day. Uteri were collected and weighed, and endometrium was recovered for total protein extraction, followed by Western blot analysis. Estrogen receptor alpha 1 (ESR1) and beta 2 (ESR2) affinity and activation by resveratrol were also determined by in vitro ESR-binding assays. Immunohistochemistry (IHC) studies were performed to visualize the proliferation marker, proliferating cell nuclear antigen (PCNA), and immunofluorescence (IF) studies were done to study the localization of PTGS2. The results showed that resveratrol increased uterine wet weight and uterine body weight ratios significantly. This local cellular proliferation in terms of the thickening of the columnar epithelial cells and an increase in the number of glands was accompanied by an increase of AKT 16 phosphorylation and PTGS2 and XIAP protein expression. These results were further supported by IF and IHC analyses. Total AKT, ESR1, and ESR2 protein expression levels were not modulated by the treatment; however, resveratrol showed moderate estrogenicity for both ESR isoforms. Expression of progesterone receptor A (PGR) was induced in the presence of resveratrol. These data support the hypothesis that resveratrol can act in a prosurvival or antiapoptotic way through AKT, XIAP, and PTGS2 regulation in the endometrium and could positively affect the outcome of pregnancy and favor fertility.