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Intracellular signaling and role of the estrogen receptors in androgen-independent prostate cancer and testicular cancer cells.

Grant number: 17/16060-3
Support type:Regular Research Grants
Duration: December 01, 2017 - May 31, 2020
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Catarina Segreti Porto
Grantee:Catarina Segreti Porto
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil


Prostate cancer initially responds well to androgen-deprivation therapies, but the majority of tumors evolve from an androgen-sensitive to an androgen-independent form of the disease, also known to castration-resistant prostate cancer (CRPC). The molecular mechanisms involved are still not well understood. The androgen-independent prostate cancer cell lines PC-3, derived from a bone metastasis of a grade IV prostatic cancer, and DU-145, derived from a brain metastasis of prostatic cancer, are currently used in vitro and in xenograft implants as CRPC models. Our laboratory has shown the expression of estrogen receptors ERalpha and ERbeta in these cells. In PC-3 cells, the activation of ERalpha and ERbeta induced phosphorylation of ERK1/2 (extracelular signal-regulated protein kinases). Furthermore, the activation of ERbeta increased the levels of non-phosphorylated beta-catenin, cyclin D2 and incorporation of [methyl-3H]thymidine. These results suggest that a novel pathway may play a role in proliferation of androgen-independent prostate cancer cell PC-3. In DU-145, the intracellular pathways coupled to these receptors need to be explored. The identification of the new signaling pathways activate by estrogen receptors will be important in development of therapeutic targets for the treatment of CRPC. Thus, the aim of this study is to investigate the effects of activation of the classical estrogen receptor ERalpha and ERbeta in the expression, cellular localization and function of the beta-catenin, SMURF1 (Smad ubiquitylation regulatory factor-1) e JNK (cJun N-terminal Kinase) in androgen-independent prostate cancer cell PC-3 and DU-145. Furthermore, the crosstalk these pathways will be explored.Testicular seminoma germ cell tumors and embryonal carcinoma (non-seminoma), originated from in situ carcinoma cells (CIS), are observed at the time of puberty in men. The development at the time of puberty these testicular tumors suggests that the induction of proliferation of CIS cells are sensitive to hormones. Thus, estrogen could play a role in this process. In fact, studies from our laboratory detected the presence of ERalpha, ERbeta and ERalpha isoform (ERalpha-36) in embryonal carcinoma cells NT2/D1. In these cells, ERalpha and ERbeta regulate cyclin D2, cyclin E and p27kip1. However, the mechanisms and the role of these receptors need to be explored in the cell cycle. In Seminoma cells, the presence of these receptors must be confirmed, as well as their functions. The aim of this study is to investigate the proliferative effects and/or anti-proliferative of 17beta-estradiol and its receptors in TCAM-2 cells (seminoma) and cells NT2 / D1 (embryonal carcinoma). Furthermore, the presence, regulation and function of ERalpha-36 in these mechanisms also will be explored. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
LOMBARDI, ANA PAOLA G.; VICENTE, CAROLINA M.; PORTO, CATARINA S. Estrogen Receptors Promote Migration, Invasion and Colony Formation of the Androgen-Independent Prostate Cancer Cells PC-3 Through beta-Catenin Pathway. FRONTIERS IN ENDOCRINOLOGY, v. 11, APR 9 2020. Web of Science Citations: 0.
SOUZA, DEBORAH S.; LOMBARDI, ANA PAOLA G.; VICENTE, CAROLINA M.; LUCAS, THAIS FABIANA G.; ERUSTES, ADOLFO G.; PEREIRA, GUSTAVO J. S.; PORTO, CATARINA S. Estrogen receptors localization and signaling pathways in DU-145 human prostate cancer cells. Molecular and Cellular Endocrinology, v. 483, p. 11-23, MAR 1 2019. Web of Science Citations: 1.

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