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- Sweet Cherries as Anti-Cancer Agents: From Bioactive Compounds to FunctionPublication . Fonseca, Lara R. S.; Silva, Gonçalo R.; Luís, Ângelo; Cardoso, Henrique J.; Correia, Sara; Vaz, CV; Duarte, Ana Paula; Socorro, SílviaSweet 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.
- Further insights into regucalcin actions as a potential tumour suppressor in human prostatePublication . Fonseca, Lara Raquel dos Santos; Socorro, Sílvia Cristina da Cruz Marques; Vaz, Cátia Alexandra Vicente; Cardoso, Henrique José Matos Morão MingoteThe calcium-binding protein regucalcin (RGN) regulates several biological processes, namely the hallmarks of cancer, such as cell proliferation and apoptosis. Previous work of our research group reported that the loss of RGN expression accompanies the onset and progression of prostate cancer (PCa). However, it remains largely unknown if the decrease of RGN expression is a cause or consequence of PCa. The present thesis aims to investigate the relationship of RGN expression levels with the hallmarks of cancer and PCa patients’ outcomes. An in silico analysis using the CancerTool3 software and patients’ datasets demonstrated that the loss of RGN correlates with the onset and progression of PCa to metastatic forms of disease. However, no correlation was found between the expression levels of RGN and the histological score of Gleason or PCa recurrence. Moreover, it was found that PCa patients with higher RGN expression levels displayed higher disease-free survival. Bioinformatic analysis of gene-to-gene expression correlation showed that the RGN gene expression in primary prostate tumours correlates directly with the expression of cyclin-dependent kinase inhibitor 1A (CDKN1A) and IL6 genes. CDKN1A gene encodes the cell cycle inhibitor p21, which has been indicated as a target of RGN in rat prostate and human cancers. No other previous study has identified a connection of RGN with IL-6 in cancer cells or tissues. Secondly, we investigated whether the loss of RGN expression may alter human prostate cell fate. Using a siRNA gene silencing approach, RGN gene expression in human non-neoplastic PNT1A cells was knockdown (KD), which was confirmed by quantitative real-time PCR. RGN gene KD increased the viability and proliferative ability of PNT1A cells as indicated by the MTT and sulforhodamine B assays’ results, and the fluorescent immunocytochemistry of the Ki-67 proliferation marker. The reduced caspase-3-like activity found in PNT1A cells KD for RGN demonstrated that the loss of this protein might contribute to apoptosis resistance. Western Blot results showed that the changes in prostate cell fate were accompanied by the altered expression of oncoproteins, such as AKT and its phosphorylated form, as well as c-myc; and also key regulators of the extrinsic pathway of apoptosis, namely, FasR, FasL and caspase-8. RGN gene KD did not alter the glycolytic metabolism of PNT1A cells, as indicated by the results of glucose consumption and lactate production. Altogether, the present findings showed that the loss of RGN expression alters the behaviour of human prostate cells and promotes the aggressiveness and progression of PCa, which supports the RGN’s role as a tumour suppressor protein. Moreover, the obtained results also support the idea that maintaining high RGN expression levels may prevent the prostate carcinogenic process and delay the progression of the disease.
- Effect of Diosgenin in Suppressing Viability and Promoting Apoptosis of Human Prostate Cancer Cells: An Interplay with the G Protein-Coupled Oestrogen Receptor?Publication . Figueira, Marília I; Marques, Ricardo; Cardoso, Henrique J.; Fonseca, Lara R. S.; Duarte, Ana Paula; Silvestre, Samuel; Socorro, SílviaDiosgenin is a phytosteroid sapogenin with reported antitumoral activity. Despite the evidence indicating a lower incidence of prostate cancer (PCa) associated with a higher consumption of phytosteroids and the beneficial role of these compounds, only a few studies have investigated the effects of diosgenin in PCa, and its mechanisms of action remain to be disclosed. The present study investigated the effect of diosgenin in modulating PCa cell fate and glycolytic metabolism and explored its potential interplay with G protein-coupled oestrogen receptor (GPER). Non-neoplastic (PNT1A) and neoplastic (LNCaP, DU145, and PC3) human prostate cell lines were stimulated with diosgenin in the presence or absence of the GPER agonist G1 and upon GPER knockdown. Diosgenin decreased the cell viability, as indicated by the MTT assay results, which also demonstrated that castrate-resistant PCa cells were the most sensitive to treatment (PC3 > DU145 > LNCaP > PNT1A; IC50 values of 14.02, 23.21, 56.12, and 66.10 µM, respectively). Apoptosis was enhanced in diosgenin-treated cells, based on the increased caspase-3-like activity, underpinned by the altered expression of apoptosis regulators evaluated by Western blot analysis, which indicated the activation of the extrinsic pathway. Exposure to diosgenin also altered glucose metabolism. Overall, the effects of diosgenin were potentiated in the presence of G1. Moreover, diosgenin treatment augmented GPER expression, and the knockdown of the GPER gene suppressed the proapoptotic effects of diosgenin in PC3 cells. Our results support the antitumorigenic role of diosgenin and its interest in PCa therapy, alone or in combination with G1, mainly targeting the more aggressive stages of the disease.
- Downregulated Regucalcin Expression Induces a Cancer-like Phenotype in Non-Neoplastic Prostate Cells and Augments the Aggressiveness of Prostate Cancer Cells: Interplay with the G Protein-Coupled Oestrogen Receptor?Publication . Fonseca, Lara R. S.; Carreira, Ricardo J. P.; Feijó, Mariana; Cavaco, J. E.; Cardoso, Henrique; Vaz, C. V.; Figueira, Marília I.; Socorro, SílviaBackground/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.