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- The G protein-coupled estrogen receptor and the calcium-binding protein regucalcin: partners against prostate cancer?Publication . Carreira, Ricardo João Pereira; Socorro, Silvia Cristina da Cruz Marques; Figueira, Marília Isabel Neto; Fonseca, Lara Raquel dos SantosProstate cancer (PCa) stands as the second most common type of cancer in men, and despite the scientific advancements, it remains a clinical and research need to identify new therapeutic targets and treatment strategies to manage this disease efficiently. The G protein-coupled estrogen receptor (GPER) is a membrane oestrogen receptor that mediates rapid non-genomic actions of oestrogenic. It has been suggested that GPER may have an anticancer role in PCa, mainly by controlling cell survival and tumour progression. However, the precise effects of GPER in PCa still need to be fully understood. Regucalcin (RGN) is a calcium (Ca2+)-binding protein that regulates Ca2+ intracellular levels and other biological functions, such as cell proliferation and apoptosis. For this reason, the outcomes of our research group and others have suggested that RGN plays a significant role in maintaining tissue homeostasis. We described the RGN cytoprotective role in prostate cells by suppressing cell proliferation and oxidative stress, which can be impactful considering PCa development. Furthermore, it was demonstrated that RGN is a target of oestrogenic regulation, likely by the role of a membrane-bound oestrogen receptor. These interconnected findings raise curiosity about the interplay between GPER and RGN. Thus, the objective of this dissertation is to investigate whether GPER mediates oestrogens’ regulation of RGN expression and to assess the impact of the GPER-RGN relationship on various cancer hallmarks in PCa. GPER gene knockdown using small interfering RNA (siRNA) downregulated RGN expression in PCa cells, whereas GPER activation by G1 had the opposite effect, which confirms the involvement of GPER in modulating RGN levels. On the other hand, the knockdown of the RGN gene did not affect GPER expression. The GPER-RGN interplay on the enhancement or suppression of cancer hallmarks was evaluated using the castration-resistant PCa (CRPC) DU145 cell line model and an approach of siRNA RGN gene knockdown followed by exposure to the GPER-specific agonist, G1. Cell viability, proliferation, apoptosis, migration, and energy metabolism were assessed using MTT assays, Ki-67 fluorescent immunocytochemistry, caspase-3 activity, Transwell assays, and spectrophotometric analysis, respectively. GPER activation resulted in decreased proliferation and increased migration in DU145 cells. RGN gene knockdown in DU145 reduced cell viability, proliferation, lactate production, and increased migration. The combination of both treatments had a higher impact on DU145 cell viability and proliferation rather than each treatment independently. Moreover, RGN gene knockdown combined with GPER activation altered glycolytic and lipid metabolism in DU145 cells. In conclusion, the present dissertation has unravelled a complex interaction between GPER and RGN in CRPC cells, demonstrating that this newly discovered ”partnership” can control PCa cell proliferation, migration, and energy metabolism. Also, this dissertation opens new avenues of research into the disclosure of the mechanisms underlying PCa development and for identifying new diagnosis and treatment strategies.