Estudo comparativo do perfil apoptótico ativado pelas vias intrínseca e extrínseca na próstata ventral de ratos Wistar durante o envelhecimento

Abstract

The growth and differentiation of the prostate gland, as well as maintenance of its components and its roles are dependent on androgens. However, estrogens also play important role in prostate growth and differentiation and participate in pathological disorders such as benign hyperplasia and adenocarcinoma, common in aging animals. Estrogens play their biological effects by binding to ER and ER receptors. ER is highly expressed in the glandular epithelium, playing important pro-apoptotic, anti-proliferative and pro-differentiation roles. Both adenocarcinoma and benign hyperplasia are related to disturbances in the balance between proliferation and cell death. The homeostasis of epithelial cells is dependent of androgens, but there is evidence that estrogens participate in this process. Confirming this fact, it is known that there is marked reduction in the expression of ER in malignant tissues or pre-malignant prostate in human and rodents. Given the known functions of ER, it is possible that silencing of these receptors may be related to the unbalance between proliferation and cell death in pathologi cal conditions. Apoptosis is a type of programmed cell death, which can be initiated by the intrinsic (dependent of caspase-9) or extrinsic (dependent of caspase-8) pathways. Evidence supports that apoptosis in the prostate can be activated by the intrinsic pathway when there is testosterone withdrawal and by extrinsic pathway when treated with ER agonist, being androgen independent and mediated by TNF. However, it is unclear if there is variation in the various components of the activation pathways of apoptosis in the prostate depending on age. Thus, our aim was to determine if there is variation in mechanisms of apoptosis in the prostate of Wistar rats in different ages (3, 6, 12, 18 and 24 months). The morphological and immunohistochemical analysis for caspase-3, caspase-9 and TUNEL showed that apoptosis is scarce in the glandular epithelium at different ages. Nevertheless, analyzes for caspase-8 showed a progressive increase in positivity with aging, preferentially at sites with atrophy or cells without morphological characteristics of apoptosis, which also have reduced expression of ER and TNF, which are pro-apoptotic factors. Thus, it is possible that low levels of TNF and ER are directing the activation of caspase-8 to its alternative pro-survival action. These data are novel and important,indicating another potential target for the prophylaxis and management of disorders involving the prostate tissue homeostasis.