Lara R. S. Fonseca

Background/Objectives: The G protein-coupled oestrogen receptor (GPER) has anti-tumorigenic effects in several human cancers. However, its role in prostate cancer (PCa) remains incompletely defined. The present study investigated GPER’s role in targeting the hallmarks of PCa. Methods: Tissue microarrays were used to analyse GPER immunoexpression in PCa samples. Non-neoplastic (PNT1A) and neoplastic (LNCaP, DU145 and PC3) prostate cells were treated with the GPER-specific agonist, G1. Cell viability, proliferation, cell cycle, apoptosis, migration and invasion were evaluated. Glucose consumption, lactate production, lactate dehydrogenase activity and oxidative status were determined spectrophotometrically. Results: GPER immunoreactivity was higher in PCa than in benign prostatic hyperplasia and inversely correlated with PSA serum levels. G1 modulated GPER subcellular location in prostate cells, being detected at the cell membrane, endoplasmic reticulum, and residually in the nucleus. GPER activation decreased cell viability and proliferation, induced cell cycle arrest at G2/M phase, and increased PCa cells apoptosis. Additionally, GPER activation inhibited the migration and invasion of DU145 cells, and long-term exposure to G1 reduced epithelial–mesenchymal transition, an effect not observed in PC3 cells, indicating the importance of cell-specific contexts. Our results also showed that G1 treatment modulated the metabolic profile of PCa cells, changing glucose, amino acids and lipid metabolism. Finally, G1 increased oxidative stress in PCa cells. Conclusions: Overall, this study demonstrated that GPER activation affects a broad range of PCa hallmarks. These findings support an anti-cancer role for GPER in PCa and encourage further exploration of its action in regulating metabolism and as a therapeutic target.

Purpose of Review: This review addresses the contribution of obesogenic endocrine-disrupting chemicals (EDCs) to prostate carcinogenesis. It provides an in-depth overview of obesogens, tracing their mechanisms of action and effects impacting prostate cell fate. The direct effects of obesogens in disrupting adipose tissue and metabolic homeostasis, as well as disturbing prostate cells, are discussed, along with the potential indirect effects mediated by the dysregulation of the adipose tissue. Recent Findings: Obesogens represent a group of EDCs that interfere with endocrine and metabolic processes, underpinning the spread of obesity. Moreover, the ubiquitous presence in the environment, the ability to accumulate in adipose tissue and the broad range of effects targeting several biological pathways highlight that obesogens can be detrimental to human health beyond their action on promoting obesity. Prostate cancer (PCa) is a hormone-dependent cancer for which environmental influences and obesity are established risk factors, with emerging evidence suggesting that obesogens may affect its development and progression. Summary: The available data indicate that obesogens may contribute to the development of PCa. They can have direct actions in prostate cells modulating signalling pathways that drive tumour aggressiveness. Moreover, the adipose tissue dysregulated by obesogens can acquire an obesity-like phenotype, which may play a crucial role in facilitating tumour growth. Further research is needed to clarify the liaison between obesogen-induced dysregulation of the periprostatic adipose tissue depot and PCa aggressiveness. Unravelling this complex crosstalk will be pivotal for identifying novel therapeutic strategies and preventing aggressive PCa, especially in obese patients.

Background: Periprostatic adipose tissue (PPAT) has been shown to play a significant role in prostate cancer (PCa) development and progression. This relationship is further exacerbated by obesity, as PPAT-secreted factors increase PCa aggressiveness and have also been implicated in chemotherapy resistance. Therefore, identifying the molecular mediators of PPAT–prostate interorgan communication and the factors that disrupt this crosstalk is pivotal for better disease management. Obesogens, i.e., endocrine-disrupting chemicals that dysregulate adipose tissue towards an “obese” phenotype, have recently been implicated in disrupting this crosstalk, with an impact on prostate cell fate. Objectives: This study aimed to investigate whether obesogenic dysregulation of human PPAT secretory activity affects PCa cell viability and their response to docetaxel and cabazitaxel. Methods/Results: Through ex vivo culture of human PPAT and conditioned medium assays, we demonstrated that exposure to the model obesogen tributyltin (TBT) induced an “obese” phenotype in human PPAT, characterised by adipocyte enlargement and increased secretion of leptin and C-C motif chemokine ligand 7. The TBT-treated PPAT secretome enhanced cell viability and decreased the sensitivity of PCa cells to taxanes. Conclusions: This study provides preliminary evidence that lays the groundwork for future investigations, dissecting the molecular pathways underpinning prostate carcinogenesis and resistance to chemotherapy induced by obesogen-dysregulated PPAT.

Background/Objectives: Regucalcin (RGN) is a calcium-binding protein and an oestrogen target gene, which has been shown to play essential roles beyond calcium homeostasis. Decreased RGN expression was identified in several cancers, including prostate cancer (PCa). However, it is unknown if the loss of RGN is a cause or a consequence of malignancy. Also, it needs confirmation if RGN oestrogenic regulation occurs through the G-protein-coupled oestrogen receptor (GPER). This study investigates how RGN knockdown affects prostate cell fate and metabolism and highlights the GPER/RGN interplay in PCa. Methods: Bioinformatic analysis assessed the relationship between RGN expression levels and patients’ outcomes. RGN knockdown (siRNA) was performed in non-neoplastic prostate and castration-resistant PCa. Wild-type and RGN knockdown PCa cells were treated with the GPER agonist G1. Viability (MTT), proliferation (Ki-67 immunocytochemistry), apoptosis (caspase-3-like activity) and migration (Transwell assays) were evaluated. Spectrophotometric analysis was used to determine glucose consumption, lactate production and lactate dehydrogenase activity. Lipid content was assessed using the Oil Red assay. Results/conclusions: Bioinformatic analysis showed that the loss of RGN correlates with the development of metastatic PCa and poor survival outcomes. RGN knockdown induced a cancer-like phenotype in PNT1A cells, indicated by increased cell viability and proliferation and reduced apoptosis. In DU145 PCa cells, RGN knockdown augmented migration and enhanced the glycolytic profile, which indicates increased aggressiveness, in line with patients’ data. GPER activation modulated RGN expression in PCa cells and RGN knockdown in DU145 cells influenced GPER actions, which highlighted an interplay between these molecular players with relevance for their potential use as biomarkers or therapeutic targets.

Sweet cherries (Prunus avium L.) are among the most appreciated fruits worldwide because of their organoleptic properties and nutritional value. The accurate phytochemical composition and nutritional value of sweet cherries depends on the climatic region, cultivar, and bioaccessibility and bioavailability of specific compounds. Nevertheless, sweet cherry extracts are highly enriched in several phenolic compounds with relevant bioactivity. Over the years, technological advances in chemical analysis and fields as varied as proteomics, genomics and bioinformatics, have allowed the detailed characterization of the sweet cherry bioactive phytonutrients and their biological function. In this context, the effect of sweet cherries on suppressing important events in the carcinogenic process, such as oxidative stress and inflammation, was widely documented. Interestingly, results from our research group and others have widened the action of sweet cherries to many hallmarks of cancer, namely metabolic reprogramming. The present review discusses the anticarcinogenic potential of sweet cherries by addressing their phytochemical composition, the bioaccessibility and bioavailability of specific bioactive compounds, and the existing knowledge concerning the effects against oxidative stress, chronic inflammation, deregulated cell proliferation and apoptosis, invasion and metastization, and metabolic alterations. Globally, this review highlights the prospective use of sweet cherries as a dietary supplement or in cancer treatment.