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- The Pros and Cons of Estrogens in Prostate Cancer: An Update with a Focus on PhytoestrogensPublication . Figueira, Marília I; Carvalho, Tiago; Monteiro, Joana; Cardoso, Henrique J.; Correia, Sara; Vaz, CV; Duarte, Ana Paula; Socorro, SílviaThe role of estrogens in prostate cancer (PCa) is shrouded in mystery, with its actions going from angelic to devilish. The findings by Huggins and Hodges establishing PCa as a hormone-sensitive cancer have provided the basis for using estrogens in therapy. However, despite the clinical efficacy in suppressing tumor growth and the panoply of experimental evidence describing its anticarcinogenic effects, estrogens were abolished from PCa treatment because of the adverse secondary effects. Notwithstanding, research work over the years has continued investigating the effects of estrogens, reporting their pros and cons in prostate carcinogenesis. In contrast with the beneficial therapeutic effects, many reports have implicated estrogens in the disruption of prostate cell fate and tissue homeostasis. On the other hand, epidemiological data demonstrating the lower incidence of PCa in Eastern countries associated with a higher consumption of phytoestrogens support the beneficial role of estrogens in counteracting cancer development. Many studies have investigated the effects of phytoestrogens and the underlying mechanisms of action, which may contribute to developing safe estrogen-based anti-PCa therapies. This review compiles the existing data on the anti- and protumorigenic actions of estrogens and summarizes the anticancer effects of several phytoestrogens, highlighting their promising features in PCa treatment.
- Prostate Cancer Metabolism in the Interplay of Obesity and Estrogens ActionsPublication . Monteiro, Joana Filipe Gomes Araújo Macário; Socorro, Sílvia Cristina da Cruz Marques; Vaz, CátiaCancers have a common ability of reprogramming energy metabolism, which is known as a hallmark of cancer. In order to satisfy their needs, cancer cells reorganized metabolic activity upregulating glycolysis rate, which allows cells to maintain high biosynthesis levels of lipids and other macromolecules, sustaining high proliferation rates. The high energy demands of cancer cells are fulfilled by anaerobic glycolysis, even in the presence of oxygen, which results in high rates of lactate production. The excess of lactate exported to the extracellular medium increases acidity and suppresses host anticancer immunity, which favours cancer cells growth and invasion. Besides glucose, fatty acids are another important energetic source, and its oxidation and biosynthesis seems to be augmented in cancer cells. Androgens are well-known drivers in development and progression of PCa. In addition, in hormone-dependent cancers, such as breast and prostate cancer, steroid hormones have been identified as important modulators of metabolic pathways. Our research group and others have demonstrated the role of androgens as stimulators of PCa by modulating glucose consumption and lactate production, as well as the distinct metabolic profile between non-neoplastic cell line, PNT1A, and neoplastic cell lines, LNCaP and PC3. However, in the last years, estrogens had also been implicated in the carcinogenesis of the prostate, despite some studies defend their protective effect. Obesity is a worldwide epidemic characterized by a disruption in adipose tissue that is associated with a stage of hyperestrogenism. In addition, obesity has been identified as a factor for aggressiveness and poor prognosis of PCa. The present work aims to evaluate the role of 17ß-Estradiol (E2) on modulating the glycolytic metabolism and lipid metabolism in human prostate cell lines, and to understand its action as stimulator of the development and progression of PCa. Non-neoplastic (PNT1A) and neoplastic (LNCaP and PC3) human prostate cell lines were cultured in presence or absence of 0,1; 1 e 100 nM de E2 for 24, 48 e 72 h. The 1 nM concentration and a treatment period of 48 h were the conditions selected to evaluate the effect of E2 on glycolytic and lipid metabolism in all cell lines under study. Protein expression and activity of target modulators of these biological processes were assessed by means of Western blot analysis and biochemical assays. The obtained results showed that treatment with E2 augmented glucose consumption and lactate production in PNT1A, LNCaP and PC3 cell lines. These results were underpinned by the increased expression or activity of glucose transporters and glycolytic enzymes. Besides that, E2-treatment increased the expression of lipid regulators in all cell lines, which demonstrate its action regulating lipid metabolism. To conclude, the obtained results showed that E2 might have a role in the development and progression of PCa by stimulating the glycolytic and lipid metabolism in both non-neoplastic and neoplastic cells. Moreover, the evidence gathered hereom follow the studies that defend the causative role of E2 in PCa. Finally, a relationship between estrogens, obesity and PCa might be likely established since hyperestrogenism may increase the odds for tumour development and invasion by potentiating the metabolic reprogramming of cancer cells.